Heterocyclic compounds as modulators of mglur7

ABSTRACT

The present invention relates to novel heterocyclic compounds. The invention is also directed to compounds which are modulators of the metabotropic glutamate receptors (mGluR), preferably of the metabotropic glutamate receptor subtype 7 (“mGluR7”). The present invention also relates to pharmaceutical composition comprising such compounds and their use for the treatment or prevention of disorders associated with glutamate dysfunction or in which metabotropic glutamate receptor, preferably mGluR7 subtype of metabotropic glutamate receptors, is involved.

This application is a continuation of U.S. application Ser. No.16/650,817, filed Mar. 25, 2020, which is a national phase applicationunder 35 U.S.C. § 371 of International Application No.PCT/EP2018/076080, filed Sep. 26, 2018, which claims benefit of EuropeanApplication No. 17306269.6, filed Sep. 26, 2017. The entire of contentsof U.S. application Ser. No. 16/650,817 and International ApplicationNo. PCT/EP2018/076080 are hereby incorporated by reference.

SUMMARY OF THE INVENTION

The present invention relates to novel heterocyclic compounds. Theinvention is also directed to compounds which are modulators of themetabotropic glutamate receptors (mGluR), preferably of the metabotropicglutamate receptor subtype 7 (“mGluR7”). The invention is also directedto pharmaceutical compositions comprising such compounds, to processesfor preparing such compounds and compositions, and to the use of suchcompounds and compositions for the prevention or treatment of disordersassociated with glutamate dysfunction or in which metabotropic glutamatereceptor, preferably mGluR7 subtype of metabotropic glutamate receptors,is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino acid neurotransmitter in the mammaliancentral nervous system (CNS) and plays a major role in severalphysiological functions, such as learning and memory, sensoryperception, development of synaptic plasticity and motor control.Furthermore, glutamate is at the centre of several neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofmGluR, belonging to class C G-protein coupled receptors (GPCRs), whichhave a modulatory role that contributes to the fine-tuning of synapticefficacy (Schoepp et al. Neuropharmacology (1999), 38:1431). Inparticular the mGlu receptor subtype 7 (mGluR7) is widely distributed inthe brain and has the highest degree of evolutionary conservation acrossspecies of all the mGlu receptors (Flor et al. Neuropharmacol. (1997),36:153). More importantly, mGluR7 has the lowest affinity for glutamate,remaining inactive during normal state of neurotransmission, onlybecoming active in severe pathophysiological conditions or during timesof excessive glutamate release (Ferraguti and Shigemoto, Cell TissueRes. (2006), 326:483). MGluR7 is thought to act as a tonic break,inhibiting further glutamate release, along influencing otherneurotransmitter release (e.g. GABA), and preventing glutamateexcitotoxicity involved in many pathologies of the CNS and sensorydisorders.

Specifically, modulators of the mGluR7, and preferably antagonists,inverse agonists and negative allosteric modulators (NAMs), are reportedto hold potential for the treatment of neurological, psychiatric, mooddisorders as well as pain and otic disorders, based on experimentalstudies on laboratory animals, deemed relevant to clinical syndromes.

Isoxazolopyridinone derivatives, including MMPIP(6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridine-4(5H)-onehydrochloride) are described as mGluR7 NAMs (Nakamura et al., Bioorg.Med. Chem. Lett. (2010), 20:726; Suzuki et al., J. Pharmacol. Exp. Ther.(2007), 323:147), and showed context-dependency pharmacology withpartial to full antagonism of the mGluR7 in vitro and in vivo (Niswenderet al., Mol. Pharmacol. (2010), 77:459; Hikichi et al., Eur. J.Pharmacol. (2010), 10, 106). MMPIP exerts also inverse agonist activitydue to constitutive activity of mGluR7 (Cieslik et al., Front. Mol.Neurosci., 20 Sep. 2018, doi:10.3389/fnmol.2018.00316).

Tetrahydrobenzoxazole derivatives, including(+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one(ADX71743) and its racemic form are described as mGluR7 NAMs or inverseagonists, and have demonstrated anxiolytic and antipsychotic activity(Kalinichev et al., J. Pharmacol. Exp. Ther. (2013), 344:624; Cieslik etal., Front. Mol. Neurosci., 20 Sep. 2018, doi:10.3389/fnmol.2018.00316).

Chromenone derivatives, including7-hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044) are described asweak mGluR7 allosteric antagonists, binding to the extracellular domainof the receptor. XAP044 has shown anxiolytic, antidepressant,anti-stress, and antipsychotic activity (Gee et al., J. Biol. Chem.(2014), 289:10975).

Combined expression of mGluR7 in brain regions and pharmacologicalmanipulations of mGluR7 in genetically-modified mice and wild-typeanimals reveals an important role for mGluR7 in numerous CNS disorders,including depression, schizophrenia, anxiety, obsessive compulsivedisorders and associated symptoms (reviewed by Pallazo et al., Curr.Neuropharmacol. (2016), 14(5): 504), and in particular in acute andchronic stress-related disorders (reviewed by Peterlik et al., CurrNeuropharmacol. (2016), 14(5): 514). Furthermore, mGluR7 represent anovel therapeutic approach for the treatment of psychostimulant (i.e.nicotine and cocaine) dependence (Li and Markou, CNS Neurol. Disord.Drug Targets (2015), 14(6):738; Li et al., Neuropharmacology (2013),66:12). In addition, mGluR7 NAM MMPIP and allosteric antagonist XAP44have shown to play a role in inhibiting pain responses, alleviatinganxiety- and depression-like behavior, and improving cognitiveperformance in neuropathic pain mice models (Pallazzo et al., Pain(2015), 156(6):1060).

It has also been shown that mGluR7 is expressed in peripheral tissuessuch as colon mucosa and stomach (Julio-Pepper et al., Pharmacol. Rev.(2011), 63:35), suggesting a potential role for treating pathologiessuch as visceral pain, stress-associated gastrointestinal dysfunctionsuch as diarrhoea or constipation in irritable bowel syndrom (IBS) orother related disorders.

Furthermore, mGluR7 is expressed in hair cells and spiral ganglionneurons of the inner ear (Friedman et al. (2008) WO2008/131439) alongwithin the vestibular system (Zhou et al., Int J Mol. Sci. (2013)14(11):22857; Horii et al., Exp. Brain Res. (2001) 139(2):188),suggesting a potential role for treating pathologies linked to the innerear and auditory nervous system. such as age-related hearing loss(presbycusis), noise-induced hearing loss, acute and chronic hearingloss, tinnitus, Meniere's disease and vestibular disorders.

It has been shown that mGluR7 is expressed at the synaptic terminals ofcertain cone bipolar cells in the retina (Brandstatter et al., (1996) J.Neurosci., 16(15):4749-4756) suggesting mGluR7 modulators are ofpotential use in the acute and chronic treatment of glaucoma and othervisual disorders.

Finally, numerous genome-wide human studies have also demonstrated theassociation of GRM7, the gene coding for the mGluR7, with severediseases such as Age-Related Hearing Loss (ARHL; presbycusis), asreported by Friedman et al. (Hum. Mol. Genet. (2009), 18:785), Van Laeret al. (Eur. J. Hum. Genet. (2010), 18:685), Newman et al. (Hear. Res.(2012), 294:125), Luo et al. (Plos One (2013), 8(10):e77153) and morerecently by Haider et al. (Front. Aging Neurosci. (2017), 9:346) andMatyas et al. (Pathol. Oncol. Res. (2018), doi:10.1007/s12253-018-0388-6); Noise-Induced Hearing Loss, as reported byLu et al. (BMC Med. Genet. (2018), 19(1):4); Tinnitus, as reported byHaider et al. (Front. Aging Neurosci. (2017), 9:346); schizophrenia, asreported by Niu et al. (Neurosci. Lett. (2015), 604:109);Attention-Deficit Hyperactivity Disorder (ADHD), as reported by Elia etal. (Nat. Genet. (2011), 44:78); major depressive disorder, as reportedby Li et al. (Eur. Neuropsychopharmacol. (2015), doi:10.1016/j.euroneuro.2015.05.004); bipolar disorders as reported byKandaswamy et al. (Am. J. Med. Genet. B. Neuropsychiatr. Genet. (2015),165B(4):365); alcohol-related addiction (Vadasz et al., Genomics (2007),90(6):690) and autistic spectrum disorders, including autism (Liu etal., Am. J. Med. Genet. B. Neuropsychiatr. Genet. (2015), 168B(4):258).

Altogether, these pharmacological and genetic data strongly support thepotential of mGluR7 modulators for the treatment of a wide range ofdisease and associated symptoms across psychiatric, neurological,neurodevelopmental, otic, pain, visual and gastrointestinal disorders.

It is an object of the invention to provide compounds having an activityon mGluR, preferably on mGluR7.

It is also an object of the invention to provide pharmaceuticalcomposition comprising such compounds.

Another object of the invention is also to provide such compounds and/orpharmaceutical composition for the treatment of diseases related tomGluR, preferably mGluR7.

DESCRIPTION OF THE INVENTION

The invention relates to compounds of Formula (I),

wherein:G is chosen among N or CR⁷,E is chosen among N or CR⁸,

-   -   provided that at least one of G or E is N

Y is CR⁹,

R¹, R², R³, R⁴, R⁵, R⁸, R⁷, R⁸ and R⁹, identical or different, are eachindependently selected in the group consisting of hydrogen, halogen,—CN, —CF₃—C(═O)R¹⁰, —C(═O)OR¹⁰, —C(═O)NR¹⁰R¹¹, —OR¹⁰, —OC(═O)R¹⁰,—OC(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —NR¹⁰R¹¹,—NR¹⁰C(═O)R¹¹, —NR¹⁰C(═O)OR¹¹, —NR¹⁰S(O)₂R¹¹, an optionally substitutedradical chosen among: —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, or—(C₁-C₆)cyanoalkyl,any two radicals R¹ and R², R³ and R⁴, and R⁵ and R⁸ may be takentogether to form an oxo (═O),wherein R¹⁰ and R¹¹ identical or different, are each independentlyselected from hydrogen, an optionally substituted radical chosen among:—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkylor —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,wherein optionally any two radicals selected from R₁, R₂, R₃, R₄, R₅,R₆, R₉, R₁₀ and R₁₁ may be taken together to form an optionallysubstituted 3 to 10-membered non-aromatic carbocyclic or heterocyclicring or a 5 to 10-membered aromatic heterocyclic ring,n is an integer selected from 0 or 1,Ar¹ is an optionally substituted aryl or heteroaryl,Ar² is an optionally substituted aryl or heteroaryl,and the N-oxide forms thereof, the pharmaceutically acceptable salts andsolvates thereof, or their optical isomers, racemates, diastereoisomers,enantiomers or tautomers thereof.

Surprisingly, the compounds of general Formula (I) demonstratemetabotropic glutamate receptor activity.

Preferably, in the compounds of Formula (I), Ar¹ represents an aryl orheteroaryl chosen among:

wherein m is the number of substituents A on the cycle and is an integerequal to 0, 1, 2, 3, 4 or 5.

Preferably, in the compounds of Formula (I), Ar² represents an aryl orheteroaryl chosen among:

wherein p is the number of substituent B on the cycle and is an integerequal to 0, 1, 2, 3, 4 or 5. It should be understood that when Ar² is abicycle, B may be on any of the two cycles.

A and B, as mentioned above, identical or different, are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —NO₂, —OH, —NH₂, —CF₃, an optionally substituted radical selectedfrom the group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₃-C₈)cycloalkenyl,—(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-aryl,—(C₁-C₆)alkylene-heterocycle, aryl, heteroaryl, heterocycle, —OR¹³,—(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,—NR¹³(C₂-C₆)alkylene-OR¹⁴, —(C₂-C₆)alkenylene-OR¹³,—(C₂-C₆)alkynylene-OR¹³, —NR¹³R¹⁴, —(C₁-C₆)alkylene-NR¹³R¹⁴,—O—(C₂-C₆)alkylene-NR¹³R¹⁴, —NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵,—(C₂-C₆)alkenylene-NR¹³R¹⁴, —(C₂-C₆)alkynylene-NR¹³R¹⁴, —SR¹³,—(C₁-C₆)alkylene-SR¹³, —O—(C₂-C₆)alkylene-SR¹³,—NR¹³—(C₂-C₆)alkylene-SR¹⁴, —S(═O)—R¹³, —(C₁-C₆)alkylene-S(═O)—R¹³,—O—(C₁-C₆)alkylene-S(═O)—R¹³, —NR¹³—(C₁-C₆)alkylene-S(═O)—R¹⁴,—S(═O)₂—R¹³, —(C₁-C₆)alkylene-S(═O)₂—R¹³, —O—(C₁-C₆)alkylene-S(═O)₂—R¹³,—NR¹³—(C₁-C₆)alkylene-S(═O)₂—R¹⁴, —S(═O)₂NR¹³R¹⁴,—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴, —O—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴,—NR¹³—(C₁-C₆)alkylene-S(═O)₂NR¹⁴R¹⁵, —NR¹³—S(═O)₂R¹⁴,—(C₁-C₆)alkylene-NR¹³—S(═O)₂R¹⁴, —O—(C₂-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—S(═O)₂R¹⁵, —C(═O)—NR¹³R¹⁴,—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴, —O—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,—NR¹³—(C₁-C₆)alkylene-C(═O)—NR¹⁴R¹⁵, —NR¹³C(═O)—R¹⁴,—(C₁-C₆)alkylene-NR¹³C(═O)—R¹⁴, —O—(C₂-C₆)alkylene-NR¹³C(═O)—R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴C(═O)—R¹⁵, —C(═O)—R¹³,—(C₁-C₆)alkylene-C(═O)—R¹³, —O—(C₁-C₆)alkylene-C(═O)—R¹³,—NR¹³—(C₁-C₆)alkylene-C(═O)—R¹⁴, —C(═O)—OR¹³,—(C₁-C₆)alkylene-C(═O)—OR¹³, —O—(C₁-C₆)alkylene-C(═O)—OR¹³,—NR¹³—(C₁-C₆)alkylene-C(═O)—OR¹⁴, —OC(═O)—R¹³,—(C₁-C₆)alkylene-OC(═O)—R¹³, —O—(C₂-C₆)alkylene-OC(═O)—R¹³,—NR¹³—(C₂-C₆)alkylene-OC(═O)—R¹⁴, —NR¹³—C(═O)—NR¹⁴R¹⁵,—(C₁-C₆)alkylene-NR¹³—C(═O)—NR¹⁴R¹⁵,—O—(C₂-C₆)alkylene-NR¹³—C(═O)—NR¹⁴R¹⁵,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—C(═O)—NR¹⁵R¹⁶, —NR¹³—C(═O)—OR¹⁴,—(C₁-C₆)alkylene-NR¹³—C(═O)—OR¹⁴, —O—(C₂-C₆)alkylene-NR¹³—C(═O)—OR¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—C(═O)—OR¹⁵, —O—C(═O)—NR¹³R¹⁴,—(C₁-C₆)alkylene-O—C(═O)—NR¹³R¹⁴, —O—(C₂-C₆)alkylene-O—C(═O)—NR¹³R¹⁴,—NR¹³—(C₂-C₆)alkylene-O—C(═O)—NR¹⁴R¹⁵, —C(═O)—(C₁-C₆)alkylene-NR¹³R¹⁴,—(C₁-C₆)alkylene-C(═O)—(C₁-C₆)alkylene-NR¹³R¹⁴,—C(═O)—(C₁-C₆)alkylene-OR¹³,—(C₁-C₆)alkylene-C(═O)—(C₁-C₆)alkylene-OR¹³, —NR¹³—C(═S)—NR¹⁴R¹⁵,—(C₁-C₆)alkylene-NR¹³—C(═S)—NR¹⁴R¹⁵, —NR¹³—C(═NR¹⁴)—NR¹⁵R¹⁶ or—(C₁-C₆)alkylene-NR¹³—C(═NR¹⁴)—NR¹⁵R¹⁶;

wherein R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently selected fromhydrogen, an optionally substituted —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl,—(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl, aryl, heterocycle,—(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-heterocycle and—(C₁-C₆)alkylene-aryl;wherein optionally any two radicals selected from R¹³, R¹⁴, R¹⁵ or R¹⁶may be taken together to form a 3 to 10-membered carbocycle,heterocycle, aryl or heteroaryl ring; wherein each ring is optionallyfurther substituted with 1 to 5 radicals independently selected fromhalogen, cyano, nitro, hydroxyl, amino, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyland —N—((C₁-C₆)alkyl)₂;wherein any two radicals A and any two radicals B may be combined withthe intervening atoms to form a 3 to 10-membered carbocycle,heterocycle, aryl or heteroaryl ring; wherein each ring is optionallyfurther substituted with 1 to 5 radicals independently selected fromhalogen, —CN, hydroxyl, amino, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and—N—((C₁-C₆)alkyl)₂.

Preferably, in the compounds of Formula (I), substituents A, identicalor different, are each independently selected from the group consistingof hydrogen, halogen, —CN, —CF₃, —OH, —NH₂, an optionally substitutedradical selected from the group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-heterocycle, heterocycle, aryl, heteroaryl, —OR¹³,—(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,—NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴, —(C₁-C₆)alkylene-NR¹³R¹⁴,—O—(C₂-C₆)alkylene-NR¹³R¹⁴, —NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —SR¹³,—(C₁-C₆)alkylene-SR¹³, —O—(C₂-C₆)alkylene-SR¹³,—NR¹³—(C₂-C₆)alkylene-SR¹⁴, —S(═O)—R¹³, —S(═O)₂—R¹³, —S(═O)₂NR¹³R¹⁴,—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴, —NR¹³—S(═O)₂R¹⁴,—(C₁-C₆)alkylene-NR¹³—S(═O)₂R¹⁴, —O—(C₂-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—S(═O)₂R¹⁵, —C(═O)—NR¹³R¹⁴,—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴, —O—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,—NR¹³—(C₁-C₆)alkylene-C(═O)—NR¹⁴R¹⁵, —NR¹³C(═O)—R¹⁴,—(C₁-C₆)alkylene-NR¹³C(═O)—R¹⁴, —O—(C₂-C₆)alkylene-NR¹³C(═O)—R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴C(═O)—R¹⁵, —C(═O)—R¹³, —C(═O)—OR¹³,—(C₁-C₆)alkylene-C(═O)—OR¹³, —O—(C₁-C₆)alkylene-C(═O)—OR¹³,—NR¹³—(C₁-C₆)alkylene-C(═O)—OR¹⁴, —OC(═O)—R¹³,—(C₁-C₆)alkylene-OC(═O)—R¹³, —O—(C₂-C₆)alkylene-OC(═O)—R¹³,—NR¹³—(C₂-C₆)alkylene-OC(═O)—R¹⁴ or —NR¹³—C(═O)—OR¹⁴;

wherein R¹³, R¹⁴ and R¹⁵ are each independently selected from hydrogen,an optionally substituted —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl, aryl, heterocycle,—(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-heterocycle and—(C₁-C₆)alkylene-aryl;wherein optionally any two radicals selected from R¹³, R¹⁴ or R¹⁵ onsubstituent A may be taken together to form a 3 to 10-memberedcarbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring isoptionally further substituted with 1 to 5 radicals independentlyselected from halogen, —CN, —NO₂, —OH, —NH₂, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;wherein any two radicals A may be combined with the intervening atoms toform a 3 to 10-membered carbocycle, heterocycle, aryl or heteroarylring; wherein each ring is optionally further substituted with 1 to 5radicals independently selected from halogen, —CN, —OH, —NH₂,—(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂.

Preferably, in the compounds of Formula (I), substituents A, identicalor different, are each independently selected from the group consistingof hydrogen, halogen, —CN, —CF₃, —OH, an optionally substituted radicalselected from the group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-heterocycle, heterocycle, —OR¹³, —(C₁-C₆)alkylene-OR¹³,—O—(C₂-C₆)alkylene-OR¹³, —NR¹³(C₂-C₆)alkylene-OR¹⁴,—O(C₂-C₆)alkylene-NR¹³R¹⁴, —NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —NR¹³R¹⁴,—(C₁-C₆)alkylene-NR¹³R¹⁴, —NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴, S(═O)₂NR¹³R¹⁴or —NR¹³—S(═O)₂R¹⁴,

wherein R¹³ and R¹⁴ are each independently selected from hydrogen, anoptionally substituted —(C₁-C₃)alkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heterocycle and—(C₁-C₆)alkylene-heterocycle;wherein optionally radicals R¹³ and R¹⁴ on substituent A may be takentogether to form a 3 to 6-membered carbocycle, heterocycle, aryl orheteroaryl ring; wherein each ring is optionally further substitutedwith 1 to 5 radicals independently selected from halogen, —CN, —OH,—NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;wherein any two radicals A may be combined with the intervening atoms toform a 3 to 10-membered carbocycle, heterocycle, aryl or heteroarylring; wherein each ring is optionally further substituted with 1 to 5radicals independently selected from halogen, —CN, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂.

Preferably, in the compounds of Formula (I), substituents A, identicalor different, are each independently selected from the group consistingof hydrogen, halogen, —CN, —CF₃, —OH, an optionally substituted radicalselected from the group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-heterocycle, heterocycle, —O—(C₁-C₆)alkyl,O—(C₁-C₃)alkyl-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-OR¹³,—O—(C₂-C₆)alkylene-OR¹³, —NR¹³R¹⁴, —(C₁-C₆)alkylene-NR¹³R¹⁴ or—NR¹³C(═O)—R¹⁴;

wherein R¹³ and R¹⁴ are each independently selected from hydrogen, anoptionally substituted —(C₁-C₃)alkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl;wherein optionally radicals R¹³ and R¹⁴ on substituent A may be takentogether to form a 3 to 6-membered carbocycle or heterocycle, whereineach ring is optionally further substituted with 1 to 5 radicalsindependently selected from halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;wherein any two radicals A may be combined with the intervening atoms toform a 3 to 10-membered carbocycle, heterocycle, aryl or heteroarylring; wherein each ring is optionally further substituted with 1 to 5radicals independently selected from halogen, —CN, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂.

Preferably, in the compounds of Formula (I), substituents A identical ordifferent, are each independently selected from the group consisting ofhydrogen, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy (—OH),cyclopropoxy, methoxymethyl, hydroxymethyl, 2-methoxyethoxy,2-hydroxyethoxy, trifluoromethyl, chloro, fluoro, cyano, dimethylamino,azetidinyl, pyrrolidinyl, morpholino, morpholinomethyl, acetamido.

Preferably, in the compounds of Formula (I), substituents B identical ordifferent, are each independently selected from the group consisting ofhydrogen, halogen, —CN, —CF₃, an optionally substituted radical selectedfrom the group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-heterocycle,—(C₁-C₆)alkylene-aryl, heterocycle, —OR¹³, —(C₁-C₆)alkylene-OR¹³,—O—(C₂-C₆)alkylene-OR¹³, —NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴,—(C₁-C₆)alkylene-NR¹³R¹⁴, —O—(C₂-C₆)alkylene-NR¹³R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —SR¹³, —(C₁-C₆)alkylene-SR¹³,—O—(C₂-C₆)alkylene-SR¹³, —NR¹³—(C₂-C₆)alkylene-SR¹⁴, —S(═O)—R¹³,—(C₁-C₆)alkylene-S(═O)—R¹³, —O—(C₁-C₆)alkylene-S(═O)—R¹³,—NR¹³—(C₁-C₆)alkylene-S(═O)—R¹⁴, —S(═O)₂—R¹³,—(C₁-C₆)alkylene-S(═O)₂—R¹³, —O—(C₁-C₆)alkylene-S(═O)₂—R¹³,—NR¹³—(C₁-C₆)alkylene-S(═O)₂—R¹⁴, —S(═O)₂NR¹³R¹⁴,—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴, —O—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴,—NR¹³—(C₁-C₆)alkylene-S(═O)₂NR¹⁴R¹⁵, —NR¹³—S(═O)₂R¹⁴,—(C₁-C₆)alkylene-NR¹³—S(═O)₂R¹⁴, —O—(C₂-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—S(═O)₂R¹⁵, —C(═O)—NR¹³R¹⁴,—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴, —O—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,—NR¹³—(C₁-C₆)alkylene-C(═O)—NR¹⁴R¹⁵, —NR¹³C(═O)—R¹⁴,—(C₁-C₆)alkylene-NR¹³C(═O)—R¹⁴, —O—(C₂-C₆)alkylene-NR¹³C(═O)—R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴C(═O)—R¹⁵, —C(═O)—R¹³,—(C₁-C₆)alkylene-C(═O)—R¹³, —O—(C₁-C₆)alkylene-C(═O)—R¹³,—NR¹³—(C₁-C₆)alkylene-C(═O)—R¹⁴, —C(═O)—OR¹³,—(C₁-C₆)alkylene-C(═O)—OR¹³, —O—(C₁-C₆)alkylene-C(═O)—OR¹³,—NR¹³—(C₁-C₆)alkylene-C(═O)—OR¹⁴, —OC(═O)—R¹³,—(C₁-C₆)alkylene-OC(═O)—R¹³, —O—(C₂-C₆)alkylene-OC(═O)—R¹³,—NR¹³—(C₂-C₆)alkylene-OC(═O)—R¹⁴, —(C₁-C₆)alkylene-NR¹³—C(═O)—NR¹⁴R¹⁵,—NR¹³—C(═O)—OR¹⁴, —(C₁-C₆)alkylene-NR¹³—C(═O)—OR¹⁴,—O—(C₂-C₆)alkylene-NR¹³—C(═O)—OR¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—C(═O)—OR¹⁵, —O—C(═O)—NR¹³R¹⁴,—(C₁-C₆)alkylene-O—C(═O)—NR¹³R¹⁴, —O—(C₂-C₆)alkylene-O—C(═O)—NR¹³R¹⁴,—NR¹³—(C₂-C₆)alkylene-O—C(═O)—NR¹⁴R¹⁵, —C(═O)—(C₁-C₆)alkylene-NR¹³R¹⁴,—C(═O)—(C₁-C₆)alkylene-OR¹³;

wherein R¹³, R¹⁴ and R¹⁵ are each independently selected from hydrogen,an optionally substituted —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl,—(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl, aryl, heterocycle,—(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-heterocycle and—(C₁-C₆)alkylene-aryl;wherein optionally any two radicals selected from R¹³, R¹⁴ or R¹⁵ onsubstituent B may be taken together to form a 3 to 10-memberedcarbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring isoptionally further substituted with 1 to 5 radicals independentlyselected from halogen, —CN, —NO₂, —OH, —NH₂, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;wherein any two radicals B may be combined with the intervening atoms toform a 3 to 10-membered carbocycle, heterocycle, aryl or heteroarylring; wherein each ring is optionally further substituted with 1 to 5radicals independently selected from halogen, —CN, —OH, —NH₂,—(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂.

Preferably, in the compounds of Formula (I), substituents B identical ordifferent, are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, —CN, an optionally substituted radical selectedfrom the group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-aryl, heterocycle,—OR¹³, —(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,—NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴, —SR¹³, —(C₁-C₆)alkylene-SR¹³,—S(═O)—R¹³, —S(═O)₂—R¹³, —NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴, —C(═O)—OR¹³,—OC(═O)—R¹³, —C(═O)—(C₁-C₆)alkylene-OR¹³ or —C(═O)—R¹³;

wherein R¹³ and R¹⁴ are each independently selected from hydrogen, anoptionally substituted —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl, aryl, heterocycle,—(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-heterocycle and—(C₁-C₆)alkylene-aryl;wherein optionally any two radicals selected from R¹³ and R¹⁴ onsubstituent B may be taken together to form a 3 to 10-memberedcarbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring isoptionally further substituted with 1 to 5 radicals independentlyselected from halogen, CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and—N—((C₁-C₆)alkyl)₂;wherein any two radicals B may be combined with the intervening atoms toform a 3 to 10-membered carbocycle, heterocycle, aryl or heteroarylring; wherein each ring is optionally further substituted with 1 to 5radicals independently selected from halogen, —CN, —OH, —NH₂,—(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂.

Preferably, in the compounds of Formula (I), substituents B, identicalor different, are each independently selected from the group consistingof hydrogen, halogen, —CF₃, an optionally substituted radical selectedfrom the group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heterocycle, —O—(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl, —O—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-OR¹³, —O—(C₁-C₆)alkylene-aryl,—O—(C₂-C₆)alkylene-O—(C₁-C₆)alkyl, —NR¹³R¹⁴ or —C(═O)—R¹³;

wherein R¹³ and R¹⁴ are each independently selected from hydrogen, anoptionally substituted —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,wherein optionally radicals R¹³ and R¹⁴ on substituent B may be takentogether to form a 3 to 6-membered carbocycle, heterocycle, aryl orheteroaryl ring; wherein each ring is optionally further substitutedwith 1 to 5 radicals independently selected from halogen, —CN, —OH,—NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;wherein any two radicals B may be combined with the intervening atoms toform a 3 to 10-membered carbocycle, heterocycle, aryl or heteroarylring; wherein each ring is optionally further substituted with 1 to 5radicals independently selected from halogen, —CN, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂.

Preferably, in the compounds of Formula (I), substituents B identical ordifferent, are each independently selected from the group consisting ofmethyl, ethyl, cyclopropyl, methoxy, ethoxy, isopropoxy, cyclopropoxy,cyclopentyloxy, benzyloxy, cyclopropylmethoxy, methoxymethyl,1-hydroxyethyl, 2-methoxyethoxy, 3-methoxypropoxy, trifluoromethyl,chloro, fluoro, dimethylamino, pyrrolidinyl, acetyl.

Preferably, in the compounds of Formula (I),

m is an integer equal to 0, 1 or 2; and/orp is an integer equal to 1, 2 or 3.

Preferably, in the compounds of Formula (I), Ar¹ represents an aryl orheteroaryl chosen among:

wherein A is defined above;wherein m is the number of substituents A on the cycle and is an integerequal to 0, 1, 2, 3 or 4.

Preferably, in the compounds of Formula (I), Ar¹ represents an aryl orheteroaryl chosen among:

pyridin-2-yl, 3-chloropyridin-2-yl, 4-chloropyridin-2-yl,5-chloropyridin-2-yl, 3-fluoropyridin-2-yl, 4-fluoropyridin-2-yl,5-fluoropyridin-2-yl, 6-fluoropyridin-2-yl, 3-methoxypyridin-2-yl,4-methoxypyridin-2-yl, 5-methoxypyridin-2-yl, 6-methoxypyridin-2-yl,3-methylpyridin-2-yl, 5-methylpyridin-2-yl, 4-methylpyridin-2-yl,6-methylpyridin-2-yl, 5-cyclopropylpyridin-2-yl, 5-hydroxypyridin-2-yl,5-(methoxymethyl)pyridin-2-yl, 5-(hydroxymethyl)pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrimidin-2-yl,pyrimidin-5-yl, 5-chloropyrimidin-2-yl, 5-fluoropyrimidin-2-yl,5-methylpyrimidin-2-yl, 4-cyclopropylpyrimidin-2-yl,5-cyclopropylpyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl,5-(trifluoromethyl)pyrimidin-2-yl, 5-(morpholinomethyl)pyrimidin-2-yl,4-methoxypyrimidin-2-yl, 5-methoxypyrimidin-2-yl,4-methoxy-5-methylpyrimidin-2-yl, 5-(2-methoxyethoxy)pyrimidin-2-yl,5-hydroxypyrimidin-2-yl, 5-(azetidin-1-yl)pyrimidin-2-yl,5-(pyrrolidin-1-yl)pyrimidin-2-yl, 4-morpholinopyrimidin-2-yl,5-morpholinopyrimidin-2-yl, thiazol-2-yl, thiazol-4-yl,1-methyl-1H-imidazol-4-yl, 5-methoxypyrazin-2-yl.

Preferably, in the compounds of Formula (I), Ar² represents an aryl orheteroaryl chosen among:

wherein B and p are as defined above.

Preferably, in the compounds of Formula (I), Ar² represents an aryl orheteroaryl chosen among:

wherein B and p are as defined above.

Preferably, in the compounds of Formula (I), Ar² represents an aryl orheteroaryl chosen among:

wherein B and p are as defined above.

Preferably, in the compounds of Formula (I), Ar² represents an aryl orheteroaryl chosen among:

2-methylphenyl, 2,4-dimethylphenyl, 2,4,6-trimethylphenyl,3-methoxy-2-methylphenyl, 4-methoxy-2-methylphenyl,5-methoxy-2-methylphenyl, 2-methoxy-3-methylphenyl,3-methoxy-4-methylphenyl, 2-methoxy-4-methylphenyl,2-methoxy-5-methylphenyl, 3-ethoxy-2-methylphenyl,3-isopropoxy-2-methylphenyl, 3-cyclopropoxy-2-methylphenyl,5-cyclopropoxy-2-methylphenyl, 3-(benzyloxy)-2-methylphenyl,3-(3-methoxypropoxy)-2-methylphenyl, 3-(2-methoxyethoxy)-2-methylphenyl,3-acetyl-2-methylphenyl, 4-acetyl-2-methylphenyl,4-chloro-2-methylphenyl, 2-methyl-5-(pyrrolidin-1-yl)phenyl,3-(dimethylamino)-2-methylphenyl, 5-methoxy-2,4-dimethylphenyl,3-cyclopropylphenyl, 3-(methoxymethyl)phenyl, 3-(dimethylamino)phenyl,(1-hydroxyethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-cyclopropoxyphenyl,5-methoxy-2-(trifluoromethyl)phenyl, 3-(cyclopentyloxy)phenyl,2,6-difluoro-3-methoxyphenyl, 2-chloro-3-methoxyphenyl,2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl,2-chloro-5-methoxyphenyl, 1-methylindolin-4-yl,1,5-dimethyl-1H-indazol-4-yl; 2-chloro-3-cyclopropoxyphenyl,1-cyclopropylindolin-4-yl, 1-cyclopropyl-1H-indol-4-yl.

Preferably, in the compounds of Formula (I), R¹, R², R³, R⁴, R⁵ and R⁶identical or different, are each independently selected from the groupconsisting of hydrogen, halogen, —OR¹⁰, —NR¹⁰R¹¹, an optionallysubstituted —(C₁-C₃)alkyl, R¹⁰ and R¹¹ being as defined previously;

wherein any two radicals R¹ and R², R³ and R⁴, and R⁵ and R⁶ may betaken together to form an oxo;wherein optionally any two radicals selected from R¹, R², R³, R⁴, R⁵ andR⁶ may be taken together to form an optionally substituted 3 to10-membered non-aromatic carbocyclic or heterocyclic ring.

Preferably, in the compounds of Formula (I), R¹, R², R³, R⁴, R⁵ and R⁶are hydrogen.

Preferably, in the compounds of Formula (I), R⁷ and R⁸ are selected fromgroups consisted of hydrogen, halogen, —CN, —OR¹⁰, —NR¹⁰R¹¹, —CF₃, anoptionally substituted —(C₁-C₃)alkyl, wherein R¹⁰ and R¹¹, identical ordifferent, are each independently selected from hydrogen, —(C₁-C₃)alkylor —(C₃-C₇)cycloalkyl, R¹⁰ and R¹¹ being as defined previously;

wherein optionally the two radicals R¹⁰ and R¹¹ may be taken together toform an optionally substituted 3 to 10-membered non-aromatic carbocyclicor heterocyclic ring.

Preferably, in the compounds of Formula (I), R⁷ and R⁸ are hydrogen.

Preferably, in the compounds of Formula (I), R⁹ is selected from groupconsisting of hydrogen, halogen, —CN, —OR¹⁰, —NR¹⁰R¹¹, —CF₃, anoptionally substituted —(C₁-C₃)alkyl, wherein R¹⁰ and R¹¹, identical ordifferent, are each independently selected from hydrogen or—(C₁-C₃)alkyl, wherein optionally the two radicals R¹⁰ and R¹¹ may betaken together to form an optionally substituted 3 to 10-memberednon-aromatic carbocyclic or heterocyclic ring.

Preferably, in the compounds of Formula (I), R⁹ is hydrogen.

Preferably, in the compounds of Formula (I) according to the invention,only one of G or E is N.

In a first preferred aspect of Formula (I), the invention provides acompound according to Formula (II):

wherein G, E, Ar¹, Ar², R¹, R², R³, R⁴, R⁵, R⁶ and Y are as definedabove for compounds of Formula (I),and the N-oxide forms thereof, the pharmaceutically acceptable salts andsolvates thereof, or their optical isomers, racemates, diastereoisomers,enantiomers or tautomers thereof.

Preferably, in the compounds of Formula (II):

-   -   Ar¹ represents an aryl or heteroaryl chosen among:

-   -   Wherein:    -   m is the number of substituents A on the cycle and is an integer        equal to 0, 1, 2, 3 or 4,    -   A, identical or different, are each independently selected from        the group consisting of hydrogen, halogen, —CN, —CF₃, —OH, —NH₂,        an optionally substituted radical selected from the group of        —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-heterocycle, heterocycle, aryl, heteroaryl,        —OR¹³, —(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,        —NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴, —(C₁-C₆)alkylene-NR¹³R¹⁴,        —O—(C₂-C₆)alkylene-NR¹³R¹⁴, —NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵,        —SR¹³, —(C₁-C₆)alkylene-SR¹³, —O—(C₂-C₆)alkylene-SR¹³,        —NR¹³—(C₂-C₆)alkylene-SR¹⁴, —S(═O)—R¹³, —S(═O)₂—R¹³,        —S(═O)₂NR¹³R¹⁴, —(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴, —NR¹³—S(═O)₂R¹⁴,        —(C₁-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,        —O—(C₂-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,        —NR¹³—(C₂-C₆)alkylene-NR¹⁴—S(═O)₂R¹⁵, —C(═O)—NR¹³R¹⁴,        —(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,        —O—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,        —NR¹³—(C₁-C₆)alkylene-C(═O)—NR¹⁴R¹⁵, —NR¹³C(═O)—R¹⁴,        —(C₁-C₆)alkylene-NR¹³C(═O)—R¹⁴,        —O—(C₂-C₆)alkylene-NR¹³C(═O)—R¹⁴,        —NR¹³—(C₂-C₆)alkylene-NR¹⁴C(═O)—R¹⁵, —C(═O)—R¹³, —C(═O)—OR¹³,        —(C₁-C₆)alkylene-C(═O)—OR¹³, —O—(C₁-C₆)alkylene-C(═O)—OR¹³,        —NR¹³—(C₁-C₆)alkylene-C(═O)—OR¹⁴, —OC(═O)—R¹³,        —(C₁-C₆)alkylene-OC(═O)—R¹³, —O—(C₂-C₆)alkylene-OC(═O)—R¹³,        —NR¹³—(C₂-C₆)alkylene-OC(═O)—R¹⁴ or —NR¹³—C(═O)—OR¹⁴;    -   wherein R¹³, R¹⁴ and R¹⁵ are each independently selected from        hydrogen, an optionally substituted —(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,        heteroaryl, aryl, heterocycle, —(C₁-C₆)alkylene-heteroaryl,        —(C₁-C₆)alkylene-heterocycle and —(C₁-C₆)alkylene-aryl;    -   wherein optionally any two radicals selected from R¹³, R¹⁴ or        R¹⁵ on substituent A may be taken together to form a 3 to        10-membered carbocycle, heterocycle, aryl or heteroaryl ring;        wherein each ring is optionally further substituted with 1 to 5        radicals independently selected from halogen, —CN, —NO₂, —OH,        —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;    -   wherein any two radicals A may be combined with the intervening        atoms to form a 3 to 10-membered carbocycle, heterocycle, aryl        or heteroaryl ring; wherein each ring is optionally further        substituted with 1 to 5 radicals independently selected from        halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and        —N—((C₁-C₆)alkyl)₂;    -   and/or    -   Ar² represents an aryl or heteroaryl chosen among:

-   -   wherein    -   p is the number of substituent B on the cycle and is an integer        equal to 0, 1, 2, 3, 4 or 5,    -   B, identical or different, are each independently selected from        the group consisting of hydrogen, halogen, —CN, —CF₃, an        optionally substituted radical selected from the group of        —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-heterocycle, —(C₁-C₆)alkylene-aryl,        heterocycle, —OR¹³, —(C₁-C₆)alkylene-OR¹³,        —O—(C₂-C₆)alkylene-OR¹³, —NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴,        —(C₁-C₆)alkylene-NR¹³R¹⁴, —O—(C₂-C₆)alkylene-NR¹³R¹⁴,        —NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —SR¹³, —(C₁-C₆)alkylene-SR¹³,        —O—(C₂-C₆)alkylene-SR¹³, —NR¹³—(C₂-C₆)alkylene-SR¹⁴, —S(═O)—R¹³,        —(C₁-C₆)alkylene-S(═O)—R¹³, —O—(C₁-C₆)alkylene-S(═O)—R¹³,        —NR¹³—(C₁-C₆)alkylene-S(═O)—R¹⁴, —S(═O)₂—R¹³,        —(C₁-C₆)alkylene-S(═O)₂—R¹³, —O—(C₁-C₆)alkylene-S(═O)₂—R¹³,        —NR¹³—(C₁-C₆)alkylene-S(═O)₂—R¹⁴, —S(═O)₂NR¹³R¹⁴,        —(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴,        —O—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴,        —NR¹³—(C₁-C₆)alkylene-S(═O)₂NR¹⁴R¹⁵, —NR¹³—S(═O)₂R′⁴,        —(C₁-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,        —O—(C₂-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,        —NR¹³—(C₂-C₆)alkylene-NR¹⁴—S(═O)₂R¹⁵, —C(═O)—NR¹³R¹⁴,        —(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,        —O—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,        —NR¹³—(C₁-C₆)alkylene-C(═O)—NR¹⁴R¹⁵, —NR¹³C(═O)—R¹⁴,        —(C₁-C₆)alkylene-NR¹³C(═O)—R¹⁴,        —O—(C₂-C₆)alkylene-NR¹³C(═O)—R¹⁴,        —NR¹³—(C₂-C₆)alkylene-NR¹⁴C(═O)—R¹⁵, —C(═O)—R¹³,        —(C₁-C₆)alkylene-C(═O)—R¹³, —O—(C₁-C₆)alkylene-C(═O)—R¹³,        —NR¹³—(C₁-C₆)alkylene-C(═O)—R¹⁴, —C(═O)—OR¹³,        —(C₁-C₆)alkylene-C(═O)—OR¹³, —O—(C₁-C₆)alkylene-C(═O)—OR¹³,        —NR¹³—(C₁-C₆)alkylene-C(═O)—OR¹⁴, —OC(═O)—R¹³,        —(C₁-C₆)alkylene-OC(═O)—R¹³, —O—(C₂-C₆)alkylene-OC(═O)—R¹³,        —NR¹³—(C₂-C₆)alkylene-OC(═O)—R¹⁴,        —(C₁-C₆)alkylene-NR¹³—C(═O)—NR¹⁴R¹⁵, —NR¹³—C(═O)—OR¹⁴,        —(C₁-C₆)alkylene-NR¹³—C(═O)—OR¹⁴,        —O—(C₂-C₆)alkylene-NR¹³—C(═O)—OR¹⁴,        —NR¹³—(C₂-C₆)alkylene-NR¹⁴—C(═O)—OR¹⁵, —O—C(═O)—NR¹³R¹⁴,        —(C₁-C₆)alkylene-O—C(═O)—NR¹³R¹⁴,        —O—(C₂-C₆)alkylene-O—C(═O)—NR¹³R¹⁴,        —NR¹³—(C₂-C₆)alkylene-O—C(═O)—NR¹⁴R¹⁵,        —C(═O)—(C₁-C₆)alkylene-NR¹³R¹⁴, —C(═O)—(C₁-C₆)alkylene-OR¹³;    -   wherein R¹³, R¹⁴ and R¹⁵ are each independently selected from        hydrogen, an optionally substituted —(C₁-C₆)haloalkyl,        —(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl, aryl,        heterocycle, —(C₁-C₆)alkylene-heteroaryl,        —(C₁-C₆)alkylene-heterocycle and —(C₁-C₆)alkylene-aryl;    -   wherein optionally any two radicals selected from R¹³, R¹⁴ or        R¹⁵ on substituent B may be taken together to form a 3 to        10-membered carbocycle, heterocycle, aryl or heteroaryl ring;        wherein each ring is optionally further substituted with 1 to 5        radicals independently selected from halogen, —CN, —NO₂, —OH,        —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;    -   wherein any two radicals B may be combined with the intervening        atoms to form a 3 to 10-membered carbocycle, heterocycle, aryl        or heteroaryl ring; wherein each ring is optionally further        substituted with 1 to 5 radicals independently selected from        halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and        —N—((C₁-C₆)alkyl)₂.

Preferably, in the compounds of Formula (II):

-   -   A, identical or different, are each independently selected from        the group consisting of hydrogen, halogen, —CN, —CF₃, —OH, an        optionally substituted radical selected from the group of        —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-heterocycle, heterocycle, —OR¹³,        —(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,        —NR¹³(C₂-C₆)alkylene-OR¹⁴, —O(C₂-C₆)alkylene-NR¹³R¹⁴,        —NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —NR¹³R¹⁴,        —(C₁-C₆)alkylene-NR¹³R¹⁴, —NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴,        S(═O)₂NR¹³R¹⁴ or —NR¹³—S(═O)₂R¹⁴,    -   wherein R¹³, R¹⁴ and R¹⁵ are each independently selected from        hydrogen, an optionally substituted —(C₁-C₃)alkyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,        heterocycle and —(C₁-C₆)alkylene-heterocycle;    -   wherein optionally radicals R¹³, R¹⁴ and R¹⁵ on substituent A        may be taken together to form a 3 to 6-membered carbocycle,        heterocycle, aryl or heteroaryl ring; wherein each ring is        optionally further substituted with 1 to 5 radicals        independently selected from halogen, —CN, —OH, —NH₂,        —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;    -   wherein any two radicals A may be combined with the intervening        atoms to form a 3 to 10-membered carbocycle, heterocycle, aryl        or heteroaryl ring; wherein each ring is optionally further        substituted with 1 to 5 radicals independently selected from        halogen, —CN, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and        —N—((C₁-C₆)alkyl)₂; and/or    -   B identical or different, are each independently selected from        the group consisting of hydrogen, halogen, —CF₃, —CN, an        optionally substituted radical selected from the group of        —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-aryl,        heterocycle, —OR¹³, —(C₁-C₆)alkylene-OR¹³,        —O—(C₂-C₆)alkylene-OR¹³, —NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴,        —SR¹³, —(C₁-C₆)alkylene-SR¹³, —S(═O)—R¹³, —S(═O)₂—R¹³,        —NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴, —C(═O)—OR¹³, —OC(═O)—R¹³,        —C(═O)—(C₁-C₆)alkylene-OR¹³ or —C(═O)—R¹³;    -   wherein R¹³ and R¹⁴ are each independently selected from        hydrogen, an optionally substituted —(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,        heteroaryl, aryl, heterocycle, —(C₁-C₆)alkylene-heteroaryl,        —(C₁-C₆)alkylene-heterocycle and —(C₁-C₆)alkylene-aryl;    -   wherein optionally any two radicals selected from R¹³ and R¹⁴ on        substituent B may be taken together to form a 3 to 10-membered        carbocycle, heterocycle, aryl or heteroaryl ring; wherein each        ring is optionally further substituted with 1 to 5 radicals        independently selected from halogen, CN, —OH, —NH₂,        —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;    -   wherein any two radicals B may be combined with the intervening        atoms to form a 3 to 10-membered carbocycle, heterocycle, aryl        or heteroaryl ring; wherein each ring is optionally further        substituted with 1 to 5 radicals independently selected from        halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and        —N—((C₁-C₆)alkyl)₂; and/or    -   only one of G or E is N.

In a second preferred aspect of Formula (I), the invention provides acompound according to Formula (III):

wherein G, E, Ar¹, Ar², R¹, R², R³, R⁴ and R⁹ are as defined above forcompounds of Formula (I),and the N-oxide forms thereof, the pharmaceutically acceptable salts andsolvates thereof, or their optical isomers, racemates, diastereoisomers,enantiomers or tautomers thereof.

Preferably, in the compounds of Formula (III),

-   -   A, identical or different, are each independently selected from        the group consisting of hydrogen, halogen, —CN, —CF₃, —OH, an        optionally substituted radical selected from the group of        —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-heterocycle, heterocycle, —OR¹³,        —(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,        —NR¹³(C₂-C₆)alkylene-OR¹⁴, —O(C₂-C₆)alkylene-NR¹³R¹⁴,        —NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —NR¹³R¹⁴,        —(C₁-C₆)alkylene-NR¹³R¹⁴, —NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴,        S(═O)₂NR¹³R¹⁴ or —NR¹³—S(═O)₂R¹⁴,    -   wherein R¹³ and R¹⁴ are each independently selected from        hydrogen, an optionally substituted —(C₁-C₃)alkyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,        heterocycle and —(C₁-C₆)alkylene-heterocycle;    -   wherein optionally radicals R¹³ and R¹⁴ on substituent A may be        taken together to form a 3 to 6-membered carbocycle,        heterocycle, aryl or heteroaryl ring; wherein each ring is        optionally further substituted with 1 to 5 radicals        independently selected from halogen, —CN, —OH, —NH₂,        —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;    -   wherein any two radicals A may be combined with the intervening        atoms to form a 3 to 10-membered carbocycle, heterocycle, aryl        or heteroaryl ring; wherein each ring is optionally further        substituted with 1 to 5 radicals independently selected from        halogen, —CN, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and        —N—((C₁-C₆)alkyl)₂; and/or    -   B identical or different, are each independently selected from        the group consisting of hydrogen, halogen, —CF₃, —CN, an        optionally substituted radical selected from the group of        —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-aryl,        heterocycle, —OR¹³, —(C₁-C₆)alkylene-OR¹³,        —O—(C₂-C₆)alkylene-OR¹³, —NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴,        —SR¹³, —(C₁-C₆)alkylene-SR¹³, —S(═O)—R¹³, —S(═O)₂—R¹³,        —NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴, —C(═O)—OR¹³, —OC(═O)—R¹³,        —C(═O)—(C₁-C₆)alkylene-OR¹³ or —C(═O)—R¹³;    -   wherein R¹³ and R¹⁴ are each independently selected from        hydrogen, an optionally substituted —(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,        heteroaryl, aryl, heterocycle, —(C₁-C₆)alkylene-heteroaryl,        —(C₁-C₆)alkylene-heterocycle and —(C₁-C₆)alkylene-aryl;    -   wherein optionally any two radicals selected from R¹³ and R¹⁴ on        substituent B may be taken together to form a 3 to 10-membered        carbocycle, heterocycle, aryl or heteroaryl ring; wherein each        ring is optionally further substituted with 1 to 5 radicals        independently selected from halogen, CN, —OH, —NH₂,        —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;    -   wherein any two radicals B may be combined with the intervening        atoms to form a 3 to 10-membered carbocycle, heterocycle, aryl        or heteroaryl ring; wherein each ring is optionally further        substituted with 1 to 5 radicals independently selected from        halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and        —N—((C₁-C₆)alkyl)₂; and/or    -   only one of G or E is N.

Preferably, in the compounds of Formula (III), G is a nitrogen and E isCR⁸, wherein R⁸ is defined as above.

Preferably, in the compounds of Formula (III), G is a nitrogen and E isCH.

The present invention also relates to a compound according to theinvention as described herein, in the form of a racemic mixture or inthe form of one or both of the individual optical isomers.

Particularly preferred compounds according to the invention includecompounds in the following list (List of Preferred Compounds), as wellas the N-oxide forms thereof, the pharmaceutically acceptable salts andsolvates thereof, or their optical isomers, racemates, diastereoisomers,enantiomers or tautomers thereof:

-   6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,-   6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (+)-6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,-   (−)-6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,-   6-(2,4-dimethylphenyl)-2-(5-chlororopyridin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one,-   2-(4-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(3-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(6-fluoropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(4-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(3-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(4-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(3-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(3-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)picolinonitrile,-   6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile,-   2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)isonicotinonitrile,-   2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile,-   6-(2,4-dimethylphenyl)-2-(5-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(4-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-(methoxymethyl)pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(pyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(pyrimidin-5-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(thiazol-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(thiazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   6-(2,4-dimethylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   2-(4-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   2-(5-hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   2-(5-(hydroxymethyl)pyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-chloropyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-methoxy-2-methylphenyl)-2-(5-methoxypyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-hydroxypyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-methoxy-2-methylphenyl)-2-(4-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(5-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(5-methoxy-2-methylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   6-(1-methylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(5-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   6-(3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-mesityl-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   6-(1-cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one-   6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-(cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   6-(3-(2-methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-(benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   2-(5-cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   2-(5-(azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,-   6-(3-methoxy-2-methylphenyl)-2-(5-(2-methoxyethoxy)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (2-(5-(2-hydroxyethoxy)-pyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one,-   7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one,-   6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one-   2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   N-(2-(6-(3-cyclopropoxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,-   (+6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (−)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   (+)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   (−)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (−)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   (−)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,-   (+)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,-   (+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   (−)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one.-   2-(5-bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,-   2-(5-bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1    (2H)-one,-   2-(5-bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,    and-   2-(5-bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one.

The present invention also relates to the following compounds of formula(IV), (V), (VI), (VII), (VIII) and (IX) as intermediates for compoundsof formula (I), (II) and (III)

wherein G, E, Ar¹, Ar², R¹, R², R³, R⁴, R⁵, R⁶ and Y are as definedabove for compounds of Formula (I), (II) and (III).

The disclosed compounds also include all pharmaceutically acceptableisotopic variations, in which at least one atom is replaced by an atomhaving the same atomic number, but an atomic mass different from theatomic mass usually found in nature. Examples of isotopes suitable forinclusion in the disclosed compounds include, without limitation,isotopes of hydrogen, such as ²H and ³H; isotopes of carbon, such as¹¹C, ¹³C and ¹⁴C; isotopes of nitrogen, such as ¹⁵N; isotopes of oxygen,such as ¹⁷O and ¹⁸O; isotopes of phosphorus, such as ³²P and ³³P;isotopes of sulfur, such as ³⁵S; isotopes of fluorine, such as ¹⁸F; andisotopes of chlorine, such as ³⁶Cl.

Use of isotopic variations (e.g., deuterium, ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements.Additionally, certain isotopic variations of the disclosed compounds mayincorporate a radioactive isotope (e.g., tritium, ³H, or ¹⁴C), which maybe useful in drug and/or substrate tissue distribution studies.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸P, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labelled compoundsof Formula (I) to (III) can generally be used as radiolabelled tracersfor imaging studies, prepared by conventional techniques known to thoseskilled in the art or by processes analogous to those described in theaccompanying Examples using appropriate isotopically-labeled reagents inplace of the non-labeled reagent previously employed.

In case of tautomeric forms, the name of the depicted tautomeric form ofthe structure was generated. However, it should be clear that the othernon-depicted tautomeric form is also included within the scope of thepresent invention.

Definition of Terms

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

In the context of the present invention, it has to be understood thatdefinitions given for each substituent of the compounds of Formula (I)apply to the corresponding substituents in compounds of Formula (II) to(III).

In addition, it has to be understood that each definition of asubstituent can be combined directly and without ambiguity with thedefinition of another substituent.

For the avoidance of doubt it is to be understood that in thisspecification “(C₁-C₆)” means a carbon radical having 1, 2, 3, 4, 5 or 6carbon atoms. “(C₀-C₆)” means a carbon radical having 0, 1, 2, 3, 4, 5or 6 carbon atoms.

In this specification “C” means a carbon atom, “N” means a nitrogenatom, “0” means an oxygen atom and “S” means a sulphur atom.

In the case where a subscript is the integer 0 (zero) the radical towhich the subscript refers, indicates that the radical is absent, i.e.there is a direct bond between the radicals.

In the case where a subscript is the integer 0 (zero) and the radical towhich the subscript refers is alkyl, this indicates the radical is ahydrogen atom.

In this specification, unless stated otherwise, the term “bond” refersto a saturated covalent bond. When two or more bonds are adjacent to oneanother, they are assumed to be equal to one bond. For example, in aradical —V—W—, wherein both V and W may be a bond, the radical isdepicting a single bond.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl radicals and may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl or t-hexyl.The term “(C₀-C₃)alkyl” refers to an alkyl radical having 0, 1, 2 or 3carbon atoms and may be methyl, ethyl, n-propyl and i-propyl.

In this specification, unless stated otherwise, the term “alkylene”includes both straight and branched difunctional saturated hydrocarbonradicals and may be methylene, ethylene, n-propylene, i-propylene,n-butylene, i-butylene, s-butylene, t-butylene, n-pentylene,i-pentylene, t-pentylene, neo-pentylene, n-hexylene, i-hexylene ort-hexylene.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted carbocycle containing noheteroatoms, including mono-, bi-, and tricyclic unsaturatedcarbocycles. Cycloalkyl includes fused ring systems and spirofused ringsystems. Examples of cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl,fluorenyl and 1,2,3,4-tetrahydronaphthalene and the like. The term“(C₃-C₇)cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and the like.

In this specification, unless stated otherwise, the term “cycloalkenyl”refers to an optionally substituted carbocycle containing noheteroatoms, including mono-, bi-, and tricyclic unsaturatedcarbocycles. The term “(C₂-C₆)cycloalkenyl” refers to a cycloalkylradical having 2 to 6 carbon atoms and one or two double bonds, and maybe, but is not limited to, cyclopentenyl and cyclohexenyl.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl radicals. The term“(C₂-C₆)alkenyl” refers to an alkenyl radical having 2 to 6 carbon atomsand one or two double bonds, and may be, but is not limited to vinyl,allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl,i-pentenyl and hexenyl.

In this specification, unless stated otherwise, the term “alkenylene”includes both straight and branched chain disubstituted alkenylradicals. The term “(C₂-C₆)alkenylene” refers to an alkenylene radicalhaving 2 to 6 carbon atoms and one or two double bonds, and may be, butis not limited to vinylene, allylene, propenylene, i-propenylene,butenylene, i-butenylene, crotylene, pentenylene, i-pentenylene andhexenylene.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl radicals. The term(C₂-C₆)alkynyl having 2 to 6 carbon atoms and one or two triple bonds,and may be, but is not limited to ethynyl, propargyl, butynyl, pentynyl,and hexynyl.

In this specification, unless stated otherwise, the term “alkynylene”includes both straight and branched chain disubstituted alkynyleneradicals. The term (C₂-C₆)alkynylene having 2 to 6 carbon atoms and oneor two triple bonds, and may be, but is not limited to ethynylene,propargylene, butynylene, pentynylene, i-pentynylene and hexynylene.

The term “aryl” refers to an optionally substituted monocyclic orbicyclic hydrocarbon ring system containing at least one unsaturated 6to 10-membered aromatic ring. Examples and suitable values of the term“aryl” are, but not limited to phenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, indyl, indenyl and the like.

In this specification, unless stated otherwise, the term “heteroaryl”refers to an optionally substituted 5 to 10-membered monocyclic orbicyclic unsaturated, aromatic ring system containing at least oneheteroatom selected independently from N, O or S. Preferably theheteroaryl comprises from 1 to 3 heteroatom, preferably chosen among N,O or S. Examples of “heteroaryl” may be, but are not limited to thienyl,pyridinyl, thiazolyl, isothiazolyl, furyl, pyrrolyl, triazolyl,imidazolyl, triazinyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl,imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl, thiadiazolyl,benzoimidazolyl, benzoxazolyl, benzothiazolyl,tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl, benzofuryl,benzothiophenyl, thionaphthyl, indolyl, isoindolyl, pyridonyl,pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, phtalazinyl,naphthyridinyl, quinoxalinyl, quinazolyl, imidazopyridinyl,oxazolopyridinyl, thiazolopyridinyl, imidazopyridazinyl,oxazolopyridazinyl, thiazolopyridazinyl, cynnolyl, pteridinyl,furazanyl, benzotriazolyl, pyrazolopyridinyl and purinyl.

In this specification, unless stated otherwise, the term“alkylene-aryl”, “alkylene-heteroaryl” and “alkylene-cycloalkyl” refersrespectively to a substituent that is attached via the alkyl radical toan aryl, heteroaryl or cycloalkyl radical, respectively. The term“(C₁-C₆)alkylene-aryl” includes aryl-(C₁-C₆)-alkyl radicals such asbenzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl,3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. The term“(C₁-C₆)alkylene-heteroaryl” includes heteroaryl-(C₁-C₆)-alkyl radicals,wherein examples of heteroaryl are the same as those illustrated in theabove definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl,3-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl,3-imidazolylmethyl, 2-oxazolylmethyl, 3-oxazolylmethyl,2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridinylmethyl,3-pyridinylmethyl, 4-pyridinylmethyl, 1-quinolylmethyl and the like. Theterm “—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl” includes—(C₃-C₇)-cycloalkyl-(C₁-C₆)-alkyl radicals, wherein examples ofcycloalkyl are the same as those illustrated in the above definition,such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclopropyethyl and the like.

In this specification, unless stated otherwise, the term “carbocyle”refers to an optionally substituted, 5 to 10-membered monocyclic,bicyclic or tricyclic saturated or partially saturated ring system aswell as fused ring systems, containing no heteroatom. Such fused ringsystems can include one ring that is partially or fully unsaturated suchas a benzene ring to form fused ring systems such as benzo-fusedcarbocycles.

In this specification, unless stated otherwise, the term “heterocycle”refers to an optionally substituted, 5 to 10-membered monocyclic orbicyclic saturated or partially saturated ring system containing atleast one heteroatom selected independently from N, O and S. Preferablythe heterocycle comprises from 1 to 3 heteroatom, preferably chosenamong N, O or S.

In this specification, unless stated otherwise, a 5- or 6-membered ringcontaining one or more atoms independently selected from C, N, O and S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to, furyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl,imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl,piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinonyl,thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl,cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.

In this specification, unless stated otherwise, a 3- to 10-membered ringcontaining one or more atoms independently selected from C, N, O and S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to imidazolidinyl, imidazolinyl,morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl,pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, dihydropyrrolylisoxazolyl, isothiazolyl, isoindolinonyl,dihydropyrrolo[1,2-b]pyrazolyl, oxazolyl, oxazolidinonyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl,pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, phenyl,cyclopropyl, aziridinyl, cyclobutyl, azetidinyl, oxadiazolyl,thiadiazolyl, tetrazolyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl.

In this specification, unless stated otherwise, the term “halo” or“halogen” may be fluoro, chloro, bromo or iodo.

In this specification, unless stated otherwise, the term “haloalkyl”means an alkyl radical as defined above, substituted with one or morehalo radicals. The term “(C₁-C₆)haloalkyl” may include, but is notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,difluoroethyl and the like.

In this specification, unless stated otherwise, the term “cyanoalkyl”means an alkyl radical as defined above, substituted with one or morecyano (CN) radicals.

In this specification, unless stated otherwise, the term “optionallysubstituted” refers to radicals further bearing one or more substituentswhich may be (C₁-C₆)alkyl, hydroxy (—OH), (C₁-C₆)alkylene-OR wherein Ris a H or (C₁-C₆)alkyl, mercapto (—SH), aryl, heteroaryl, heterocycle,(C₁-C₆)alkylene-aryl, (C₁-C₆)alkylene-heterocycle,(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, (C₁-C₆)alkylene-heteroaryl, halogen,trifluoroalkyl (preferably trifluoromethyl), trifluoroalkoxy (preferablytrifluoromethoxy), cyano (CN), cyanoakyl (preferably cyanomethyl), nitro(NO₂), amino (NH₂), carboxyl (CO₂H), carboxamide (CONH₂), carbamate(NH—C(═O)OR wherein R is a (C₁-C₆)alkyl, sulfonamide (S(═O)₂—NH₂), esterof formula C(O)OR wherein R is a (C₁-C₆)alkyl, and sulfonyl (S(═O)—R)wherein R is a (C₁-C₆)alkyl.

As used herein, the expression “pharmaceutically acceptable” refers tothose compounds, materials, excipients, compositions or dosage formswhich are, within the scope of sound medical judgment, suitable forcontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. The pharmaceutically acceptable saltsinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like,including mono, di or tri-salts thereof; and the salts prepared fromorganic acids such as acetic, propionic, succinic, tartaric, citric,methanesulfonic, benzenesulfonic, glucoronic, glutamic, benzoic,salicylic, toluenesulfonic, oxalic, fumaric, maleic, lactic and thelike. Further addition salts include ammonium salts such astromethamine, meglumine, epolamine, etc., metal salts such as sodium,potassium, calcium, zinc or magnesium.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. Generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 20^(th) ed., Mack Publishing Company, Easton,Pa., 2000, the disclosure of which is hereby incorporated by reference.

As used herein, “pharmaceutically acceptable solvate” refer toderivatives of the disclosed compounds wherein the parent compound ismodified by making a solvate thereof. In this specification, unlessstated otherwise, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (e.g. a compound of Formula (I)) and asolvent. The invention embraces solid forms of the compounds of Formula(I) in any solvated form, including e.g. solvates with water, forexample hydrates, or with organic solvents such as, e.g., methanol,ethanol or acetonitrile, referred as a methanolate, ethanolate oracetonitrilate, respectively; or in the form of any polymorph. Suchsolvent may not interfere with the biological activity of the solute.

Pharmaceutically acceptable prodrugs of compounds that can be used inthe present invention, in particular the compounds of Formula (I), arederivatives which have chemically or metabolically cleavable groups andbecome, by solvolysis or under physiological conditions, the compoundsused in the present invention which are pharmaceutically active in vivo.Prodrugs of compounds that can be used in the present invention may beformed in a conventional manner with a functional group of the compoundssuch as with an amino, hydroxy or carboxy group. The prodrug derivativeform often offers advantages of solubility, tissue compatibility ordelayed release in a mammal, including human (see, Bundgaard, H., Designof Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well known to the person skilled in the art, such asesters prepared by reaction of the parent acidic compound with asuitable alcohol, or amides prepared by reaction of the parent acidcompound with a suitable amine. When a compound employed in the presentinvention, in particular a compound of Formula (I), has a carboxylgroup, an ester derivative prepared by reacting the carboxyl group witha suitable alcohol or an amide derivative prepared by reacting thecarboxyl group with a suitable amine is exemplified as a prodrug. Anespecially preferred ester derivative as a prodrug is methylester,ethylester, n-propylester, i-propylester, n-butylester, or i-butylester.When a compound employed in the present invention has a hydroxy group,an acyloxy derivative prepared by reacting the hydroxy group with asuitable acylhalide or a suitable acid anhydride is exemplified as aprodrug. When a compound employed in the present invention has an aminogroup, an amide derivative prepared by reacting the amino group with asuitable acid halide or a suitable mixed anhydride is exemplified as aprodrug.

The compounds of Formula (I) or pharmaceutically acceptable salts,solvates or prodrugs thereof, may be administered as compounds per se ormay be formulated as medicaments. Within the scope of the presentinvention are pharmaceutical compositions comprising as an activeingredient one or more compounds of Formula (I), or pharmaceuticallyacceptable salts, solvates or prodrugs thereof. The pharmaceuticalcompositions may optionally comprise one or more pharmaceuticallyacceptable excipients, such as carriers, diluents, fillers,disintegrants, lubricating agents, binders, colorants, pigments,stabilizers, preservatives, or antioxidants.

The pharmaceutical compositions may also comprise one or more solubilityenhancers, such as, e.g., poly(ethylene glycol), including poly(ethyleneglycol) having a molecular weight in the range of about 200 to about5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants,tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, phospholipids,lecithin, dimyristoyl phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrins,hydroxyethyl-3-cyclodextrin, hydroxypropyl-3-cyclodextrin,hydroxyethyl-γ-cyclodextrin, hydroxypropyl-Y-cyclodextrin,dihydroxypropyl-3-cyclodextrin, glucosyl-a-cyclodextrin,glucosyl-3-cyclodextrin, diglucosyl-3-cyclodextrin,maltosyl-a-cyclodextrin, maltosyl-3-cyclodextrin,maltosyl-Y-cyclodextrin, maltotriosyl-3-cyclodextrin,maltotriosyl-γ-cyclodextrin, dimaltosyl-3-cyclodextrin,methyl-3-cyclodextrin, carboxyalkyl thioethers, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinylacetate copolymers, vinyl pyrrolidone, sodium lauryl sulfate, dioctylsodium sulfosuccinate, or any combination thereof.

In this specification, unless stated otherwise, certain compounds mayexist in one or more particular geometric, optical, enantiomeric,diastereoisomeric, epimeric, stereoisomeric, tautomeric, conformational,or anomeric forms, including, but not limited to, cis- and trans-forms;E- and Z-forms; endo- and exo-forms, R-, S-, and meso-forms; D- andL-forms; d- and l-forms; (+) and (−) forms; keto-, enol-, andenolate-forms; α- and β-forms; axial and equatorial forms; andcombinations thereof, collectively referred to as “isomers” or “isomericforms”. Note that specifically included in the term “isomer” arecompounds with one or more isotopic substitutions. For example, H may bein any isotopic form, including, but not limited to, ¹H, ²H (D), and ³H(T); C may be in any isotopic form, including, but not limited to, ¹¹C,¹²C, ¹³C, ¹⁴C; O may be in any isotopic form, including, but not limitedto, ¹⁶O and ¹⁸O; and the like. F may be in any isotopic form, including,but not limited to, ¹⁹F and ¹⁸F; and the like.

The present invention also related to composition, preferablypharmaceutical composition, comprising at least one compound accordingto the invention. Preferably, the compound according to the invention iscontained in the composition in a therapeutically effective amount.“Therapeutically effective amount” means an amount of acompound/medicament according to the present invention effective inpreventing or treating a pathological condition.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, using conventionaltechniques and by observing results obtained under analogouscircumstances. In determining the therapeutically effective amount, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of subject; its size, age,and general health; the specific disease involved; the degree ofinvolvement or the severity of the disease; the response of theindividual subject; the particular compound administered; the mode ofadministration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The composition may further comprise a pharmaceutically acceptableexcipient. The carrier or diluent must be “acceptable” in the sense ofbeing compatible with the other ingredients of the composition and notdeleterious to the recipients thereof.

“Pharmaceutically” or “pharmaceutically acceptable” refer to molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate.

As used herein, “pharmaceutically acceptable excipient” includes anycarriers, diluents, adjuvants, or vehicles, such as preserving orantioxidant agents, fillers, disintegrating agents, wetting agents,emulsifying agents, suspending agents, solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutical active substances is well-known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions as suitable therapeutic combinations.

The composition may be in various pharmaceutical forms foradministration purposes. As appropriate compositions there may be citedall compositions usually employed for systemically or locallyadministering drugs.

The pharmaceutical compositions of this invention may be prepared by anymethods well known in the art of pharmacy, for example, using methodssuch as those described in Gennaro et al. Remington's PharmaceuticalSciences (18th ed., Mack Publishing Company, 1990, see especially Part8: Pharmaceutical preparations and their Manufacture). To prepare thepharmaceutical compositions of this invention, a therapeuticallyeffective amount of the particular compound, optionally in salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier or diluent, which carrier or diluentmay take a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, in particular, for oral,topical, rectal or percutaneous administration, by parenteral injection,by middle or inner ear administration, or by inhalation.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, teaspoonfuls, tablespoonfuls, and segregated multiplesthereof.

Since the compounds according to the invention are orally administrablecompounds, pharmaceutical compositions comprising said compounds fororal administration are especially advantageous.

In order to enhance the solubility and/or the stability of the compoundsaccording to the invention in pharmaceutical compositions, it can beadvantageous to employ α-, β- or γ-cyclodextrins or their derivatives,in particular hydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-cyclodextrin or sulfobutyl-cyclodextrin. Also,co-solvents such as alcohols may improve the solubility and/or thestability of the compounds according to the invention in pharmaceuticalcompositions.

The present invention also relates to a process for preparing thepharmaceutical composition according to the invention, characterized inthat a pharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of a compound according to theinvention.

The present invention relates to the compounds described above for itsuse as a medicament.

The present invention also relates to the use of the compounds accordingto the invention or a composition according to the invention for thepreparation of a medicinal product or a medicament.

The inventors have surprisingly found that the compounds described aboveare modulators of mGlu receptors, preferably modulators of mGluR7,preferably antagonists of mGluR7.

Accordingly, the present invention relates to the compounds according tothe invention, or the composition according to the invention, for itsuse to modulate, preferably to reduce or inhibit or negatively modulate,the activity of mGlu receptors, in particular mGluR7.

The invention also relates to the use of the compounds according to theinvention or of the composition according to the invention, for thepreparation of a medicine to modulate, preferably to reduce or inhibitor negatively modulate, the activity of mGlu receptors, in particularmGluR7.

The present invention also relates to a method to modulate, preferablyto reduce or inhibit or negatively modulate, the activity of mGlureceptors, in particular mGluR7, comprising the administration, to apatient in need thereof, of a therapeutically effective amount of thecompounds according to the invention or of the composition according tothe invention.

According to the invention, the terms “patient” or “patient in needthereof”, are intended for an animal or a human being affected or likelyto be affected with a pathological condition involving an activecysteine protease in its pathogenesis. Preferably, the patient is human.

The identification of those subjects who are in need of treatment ofherein-described diseases and conditions is well within the ability andknowledge of one skilled in the art. A veterinarian or a physicianskilled in the art can readily identify, by the use of clinical tests,physical examination, medical/family history or biological anddiagnostic tests, those subjects who are in need of such treatment.

The present invention also relates to the compounds according to theinvention, or the composition according to the invention, for its usefor treating diseases associated with glutamate dysfunction.

The present invention also relates to the use of the compounds accordingto the invention, or the composition according to the invention, for thepreparation of a medicine for the treatment of diseases associated withglutamate dysfunction.

In particular, the present invention thus also relates to a compoundaccording to the invention or a composition according to the inventionfor its use for the prevention or treatment of disorders associated withglutamate dysfunction in a mammal, including a human.

The present invention also relates to a method for the treatment ofdiseases associated with glutamate dysfunction comprising theadministration, to a patient in need thereof, of a therapeuticallyeffective amount of the compounds according to the invention or of thecomposition according to the invention.

As used herein, the term “treatment” is intended to refer to allprocesses, wherein there may be a slowing, interrupting, arresting orstopping of the progression of a disease or an alleviation of symptoms,but does not necessarily indicate a total elimination of all symptoms.

The present invention also relates to the compounds of the invention, orthe composition of the invention, for the use for the prevention ortreatment of anxiety disorders such as agoraphobia, generalized anxietydisorder (GAD), obsessive-compulsive disorder (OCD), panic disorder,post-traumatic stress disorder (PTSD), social phobia, other phobias;mood disorders including bipolar disorders (I & II), cyclothymicdisorder, depression, dysthymic disorder, major depressive disorder,substance-induced mood disorder, mood disorder due to a general medicalcondition, mania, manic depression, seasonal affective disorders;muscular spasms and disorders associated with muscular spasticityincluding tremors, epilepsy, convulsions, migraine; disorders selectedfrom the group consisting of neurodegenratives disorders such asmild-cognitive impairment, Alzheimer's disease, Parkinson's disease,multiple sclerosis and amyotrophic lateral sclerosis; disorders selectedfrom the group consisting of psychotic disorders such as schizophrenia,delusional disorder, schizoaffective disorder, schizophreniformdisorder, substance-induced psychotic disorder; personality disordersincluding obsessive-compulsive personality disorder, schizoid,schizotypal disorder, borderline personality disorder, anxious-avoidantpersonality disorder; childhood disorders includingattention-deficit/hyperactivity disorder, mental retardation, Down'ssyndrome, tics disorders, autistic spectrum disorders (such as Rettsyndrome or Fragile X syndrome) and autism; otic disorders includinginner ear diseases, disorders, impairments or conditions, such assensorineural hearing loss, age-related hearing impairment(presbycusis), Meniere's disease, sudden hearing loss, noise-inducedhearing loss, drug-induced hearing loss, hidden hearing loss,cisplatin-induced hearing loss, aminoglycosides-induced hearing loss,otitis media, ototoxicity, autoimmune inner ear disease, acute tinnitus,chronic tinnitus, central auditory processing disorders and vestibulardisorders; disorders of the gastrointestinal tract including diarrhoea,constipation, gastro-esophageal reflux disease (GERD), lower esophagealsphincter diseases or disorders, diseases of gastrointestinal motility,colitis, Crohn's disease or irritable bowel syndrome (IBS); paindisorders including acute pain, chronic pain, severe pain, intractablepain, inflammatory pain, post-operative pain, headache pain, cancerpain, neuropathic pain, post-traumatic pain, and visceral pain;cognitive deficit and mood disorders associated with the aforementioneddisorders; ocular disorders including ocular hypertension, glaucoma,normal tension glaucoma, neurodegenerative disease conditions of theretina and the optic nerve, retinal dystrophies, age-related Maculardegeneration, and conditions of the eye such as conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, inflammationand/or neurodegeneration; disorders resulting from traumatic braininjury, stroke, hemorrhagic stroke, ischemia, spinal cord injury,cerebral hypoxia, cerebral hemorrhage or intracranial hematoma.

In particular the present invention relates to the compounds of theinvention, or the composition of the invention, for the use for theprevention or treatment of certain neurological and psychiatricdisorders such as anxiety disorders, including but not limited tophobias, generalized anxiety disorders (GAD), panic disorder, obsessivecompulsive disorders (OCD), acute and chronic stress-related disorders(such as post-traumatic stress disorders (PTSD); mood disorders,including but not limited to major depressive disorder, depression andtreatment resistant depression, mania, bipolar disorders; amnestic andother cognitive disorders; disorders usually first diagnosed in infancy,childhood or adolescence, including but not limited to attention-deficitdisorder such as Attention-Deficit/Hyperactivity Disorder, mentalretardation, learning disorders, autistic spectrum disorder (such asRett syndrome or Fragile X syndrome); substance-related disorders,including but not limited to alcohol dependence, alcohol abuse, drugdependence and drug abuse; schizophrenia and other psychotic disorders;somatoform disorders; sleep disorders; muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, migraine; and traumatic brain injury.

In particular the present invention relates to the compounds of theinvention, or the composition of the invention, for the use for theprevention or treatment of certain neurodegenerative conditions ordiseases such as mild-cognitive impairment, dementia, Alzheimer'sdisease and Parkinson's disease.

In particular the present invention relates to the compounds of theinvention, or the composition of the invention, for the use for theprevention or treatment of certain pain conditions or diseases such asacute pain, chronic pain, neuropathic pain, post-traumatic pain, andvisceral pain.

In particular the present invention relates to the compounds of theinvention, or the composition of the invention, for the use for theprevention or treatment of otic disorders, including age-related hearingloss (or presbycusis), noise-induced hearing loss, cisplatin-inducedhearing loss, aminoglycosides-induced hearing loss, acute and chronictinnitus, central auditory processing disorders and vestibulardisorders.

The present invention also relates to a compound according to theinvention or a composition according to the invention, for its use forthe prevention or treatment of anxiety disorders, post-traumatic stressdisorders, obsessive compulsive disorders, panic disorders, depression,bipolar disorders, schizophrenia, autistic spectrum disorder, oticdisorders and pain.

All the diseases mentioned above are considered to be diseasesassociated with glutamate dysfunction according to the invention.

As already mentioned hereinabove, the term “treatment” does notnecessarily indicate a total elimination or prevention of all symptomsbut may also refer to symptomatic treatment or prophylactic interventionin any of the disorders mentioned above. In particular, symptoms thatmay be treated or prevented include but are not limited to, cognitivedeficit, fear behavior, hypervigilance, aggressive behaviour, hearingdeficit, pain, in particular in anxiety disorders, acute stressdisorder, chronic stress disorder, post-traumatic stress disorder,schizophrenia, otic disorders and pain disorder.

The person skilled in the art will recognize that alternativenomenclatures, nosologies, and classification systems for disordersdescribed herein exist, and that these evolve with medical andscientific progresses.

The invention also relates to the use of a compound according to theinvention as a radiolabeled tracer for imaging metabotropic glutamatereceptors, preferably mGluR7 in mammal, including human.

The invention also relates to a compound according to the generalFormula (I), (II), (Ill), or a stereoisomeric form thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or a solvatethereof, in particular, a compound of Formula (I), (II), (Ill), or astereoisomeric form thereof, or a pharmaceutically acceptable salt or asolvate thereof, or a pharmaceutical composition according to theinvention, for use for the treatment or prevention of, in particulartreatment of, a condition in a mammal, including a human, the treatmentor prevention of which is affected or facilitated by the neuromodulatoryeffect of the compounds according to the invention on mGluR, especiallymGluR7.

The present invention also relates to a compound according to theFormula (I) for use in the treatment, prevention, amelioration, controlor reduction of the risk of various neurological and psychiatricdisorders associated with glutamate dysfunction in a human, thetreatment or prevention of which is affected or facilitated by theneuromodulatory effect of the compounds according to the invention onmGlu receptors, especially mGluR7.

The invention also relates to a method for the treatment or preventionof, in particular treatment of, a condition in a mammal, including ahuman, the treatment or prevention of which is affected or facilitatedby the neuromodulatory effect of the compounds according to theinvention on mGluR, especially mGluR7, comprising administering to aperson in need thereof of a therapeutically effective amount of compoundaccording to the general Formula (I), (II), (Ill), or a stereoisomericform thereof, or an N-oxide thereof, or a pharmaceutically acceptablesalt or a solvate thereof, in particular, a compound of Formula (I),(II), (Ill), or a stereoisomeric form thereof, or a pharmaceuticallyacceptable salt or a solvate thereof, or a pharmaceutical compositionaccording to the invention.

The present invention also relates to a method for the treatment,prevention, amelioration, control or reduction of the risk of variousneurological and psychiatric disorders associated with glutamatedysfunction in a human, the treatment or prevention of which is affectedor facilitated by the neuromodulatory effect of the compounds accordingto the invention on mGlu receptors, especially mGluR7 compound accordingto the Formula (I).

The present invention also relates to a compound according to theFormula (I), (II), (Ill), or a stereoisomeric form thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or a solvatethereof, in particular, a compound of Formula (I), (II), (Ill), or astereoisomeric form thereof, or a pharmaceutically acceptable salt or asolvate thereof, for the treatment or prevention, in particulartreatment, of any one of the diseases mentioned hereinbefore.

The present invention also relates to the use of a compound according tothe Formula (I), (II), (III), or a stereoisomeric form thereof, or anN-oxide thereof, or a pharmaceutically acceptable salt or a solvatethereof, in particular, a compound of (I), (II), (Ill), or astereoisomeric form thereof, or a pharmaceutically acceptable salt or asolvate thereof, for the preparation of a medicine or medicinal product,for treatment or prevention, in particular treatment, of any one of thediseases mentioned hereinbefore.

The compounds of the present invention can be administered to mammals,preferably humans, for the treatment or prevention of any one of thediseases mentioned hereinbefore.

Therefore, the invention also relates to a method for the preventionand/or treatment of any one of the diseases mentioned hereinbeforecomprising administering, to a patient in need thereof, atherapeutically effective amount of a compound according to theinvention to a subject in need thereof.

One skilled in the art will recognize that a therapeutically effectiveamount of the compounds of the present invention is the amountsufficient to modulate, inhibit or reduce the activity of the mGluR,especially mGluR7, and that this amount varies, depending on the type ofdisease, the concentration of the compound in the therapeuticformulation, and the condition of the patient. In general, an amount ofcompound to be administered as a therapeutic agent for treating diseasesin which modulation, inhibition or reduction of mGluR activity,preferably of the mGluR7, is beneficial, such as the disorders describedherein, will be determined on a case by case by an attending physician.

In general, a suitable dose is one that results in a concentration ofthe compounds in the range of 0.5 nM to 200 μM, and more usually 5 nM to50 μM. To obtain these treatment concentrations, a patient in need oftreatment likely will be administered an effective therapeutic dailyamount of about 0.01 mg/kg to about 50 mg/kg body weight, preferablyfrom about 0.01 mg/kg to about 25 mg/kg body weight, more preferablyfrom about 0.01 mg/kg to about 10 mg/kg body weight, more preferablyfrom about 0.01 mg/kg to about 2.5 mg/kg body weight, even morepreferably from about 0.05 mg/kg to about 1 mg/kg body weight, morepreferably from about 0.1 to about 0.5 mg/kg body weight. The amount ofa compound according to the present invention, also referred to here asthe active ingredient, which is required to achieve a therapeuticallyeffect will, of course vary on case-by-case basis, vary with theparticular compound, the route of administration, the age and conditionof the recipient, and the particular disorder or disease being treated.A method of treatment may also include administering the activeingredient on a regimen of between one and four intakes per day. Inthese methods of treatment, the compounds according to the invention arepreferably formulated prior to admission. As described herein below,suitable pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients.

Combination Therapy

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditionsaforementioned for which compounds of the invention or the other drugsmay have utility, where the combination of the drugs together are saferor more effective than either drug alone. In another aspect, the presentinvention relates to a combination therapy in which an active compoundaccording to the present invention is administered together with anotheractive compound. Such combinations may be fixed dose combinations (theactive ingredients that are to be combined are subject of the samepharmaceutical formulation) or free dose combinations (activeingredients are in separate pharmaceutical formulations). Consequently,a further aspect of the present invention refers to a combination ofeach of the active compounds of the present invention, preferably atleast one active compound according to the present invention, withanother active compound, that modulate receptors or enzymes in a mannersuch that the efficacy and/or safety of the active compounds accordingto the invention is increased and/or unwanted side effects are reduced.The different drugs of such a combination or product may be combined ina single preparation together with pharmaceutically acceptable carriersor diluents, or they may each be present in a separate preparationtogether with pharmaceutically acceptable carriers or diluents.

Because modulators of mGluR, preferably of mGluR7, including compoundsof the invention, modulate the response of mGluR, preferably mGluR7, toendogenous glutamate and/or mGluR7 agonists and/or Group III agonists,it is understood that the present invention extends to the treatment ofdisorders associated with glutamate dysfunction by administering aneffective amount of a modulator of mGluR7, including compounds of theinvention, in combination with an mGluR7 agonist and/or a Group IIImGluR agonist.

The compounds of the present invention may also be utilized incombination with psychotherapies in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions, for whichcompounds of the invention may have utility.

The present invention also relates to pharmaceutical compositionaccording to the invention further comprising another compound whichmodulates the activity of mGluR, preferably which inhibits or reducesthe activity of mGluR, preferably mGluR being mGluR7.

The present invention also relates to a kit comprising:

-   -   At least one compound according to the invention or a        pharmaceutical composition comprising at least a compound        according to the invention; and    -   At least another compound which modulates the activity of mGluR,        preferably which inhibits or reduces the activity of mGluR,        preferably mGluR being mGluR7 or a pharmaceutical composition        comprising at least a compound which modulates the activity of        mGluR, preferably which inhibits or reduces the activity of        mGluR, preferably mGluR being mGluR7.

Dosage

The exact dosage (or as herein mentioned therapeutically effectiveamount) and frequency of administration depends on the particularcompound of the invention used, the particular condition being treated,the severity of the condition being treated, the age, weight, sex,extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% byweight, more preferably from 0.1 to 50% by weight of the activeingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9%by weight, more preferably from 50 to 99.9% by weight of apharmaceutically acceptable carrier, all percentages being based on thetotal weight of the composition.

The amount of a compound according to the invention that can be combinedwith a carrier material to produce a single dosage form will varydepending upon the disease treated, the mammalian species, and theparticular mode of administration. However, as a general guide, suitableunit doses for the compounds of the present invention can, for example,preferably contain between 0.1 mg to about 1000 mg of the activecompound. A preferred unit dose is between 1 mg to about 500 mg. A morepreferred unit dose is between 1 mg to about 300 mg. Even more preferredunit dose is between 1 mg to about 100 mg.

Such unit doses can be administered more than once a day, for example,2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, sothat the total dosage for a 70 kg adult is in the range of 0.001 toabout 15 mg per kg weight of subject per administration. A preferreddosage is 0.01 to about 1.5 mg per kg weight of subject peradministration, and such therapy can extend for a number of weeks ormonths, and in some cases, years. It will be understood, however, thatthe specific dose level for any particular patient will depend on avariety of factors including the activity of the specific compoundemployed; the age, body weight, general health, sex and diet of theindividual being treated; the time and route of administration; the rateof excretion; other drugs that have previously been administered; andthe severity of the particular disease undergoing therapy, as is wellunderstood by those of skill in the area.

A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about300 mg taken once a day, or, multiple times per day, or one time-releasecapsule or tablet taken once a day and containing a proportionallyhigher content of active ingredient. The time-release effect can beobtained by capsule materials that dissolve at different pH values, bycapsules or gel formulations that release slowly by osmotic pressure, orby any other known means of controlled release.

It can be necessary to use dosages outside these ranges in some cases aswill be apparent to those skilled in the art. Further, it is noted thatthe clinician or treating physician will know how and when to start,interrupt, adjust, or terminate therapy in conjunction with individualpatient response.

Preparation of Compounds A. Methods of Synthesis

The compounds according to the invention, in particular the compoundsaccording to the Formula (I), (II) and (III) may be prepared by methodsknown to the person skilled in the art of organic synthesis or by usingthe following synthesis schemes. In all of the schemes described belowit is understood that protecting groups for sensitive or reactive groupsare employed where necessary in accordance with the general principlesof organic chemistry. Protecting groups are manipulated according tostandard methods (T. W. Green and P. G. M. Wuts, 1991, Protecting Groupsin Organic Synthesis, John Wiley & Sons, Inc.). These groups are thenremoved at a convenient stage of the synthesis using methods that arereadily apparent to those skilled in the art.

The compounds according to the invention may be represented as a mixtureof enantiomers which may be resolved into their individual R- orS-enantiomers. If for instance, a particular enantiomer is required itmay be obtained by separation from the racemic mixture by using chiralchromatography techniques, or prepared by asymmetric synthesis or byderivation with a chiral auxiliary and the resulting diastereomericmixture separated. The auxiliary group can then be cleaved to providethe desired pure enantiomers. Alternatively, where the molecule containsa basic functional group such as an amino functional group or an acidicfunctional group such as a carboxyl functional group, resolution may beperformed by fractional crystallization from various solvents as thesalt of an optical active acid or by other methods known in theliterature.

Resolution of the final product, an intermediate or a starting materialmay be performed by any suitable method known in the art (E. L. Eliel,S. H. Wilen and L. N. Mander, 1984, Stereochemistry of OrganicCompounds, Wiley-Interscience).

Many of the heterocyclic compounds of Formula (I) to (III) where Ar¹ orAr² is a heteroaromatic or heterocyclic group may be prepared usingsynthetic routes well known in the art (A. R. Katrizky and C. W. Rees,1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

The synthesis of mGluR modulators disclosed in the present inventionhave been prepared using the following synthetic schemes. Specificconditions for carrying out these reactions are provided in theexamples. The synthetic schemes described below show exemplifiedapproaches to compounds of the present invention, but these routesshould not be taken as the only possible synthetic routes to compoundsof the present invention.

Compounds of Formula (I) to (III) may be converted in their pureenantiomeric forms (+) and (−) using for example chiral separation.

Compounds of Formula (I), (II) and (III) wherein R⁹ is hydrogen, may beobtained according to Scheme 1 below:

Cyclic ketone intermediates 1 are commercially available or may besynthesized by a person skilled in the art of organic chemistry usingmultiple ways described in the literature.

Secondary alcohol intermediates 2 may be obtained by nucleophilicaddition of an organometallic Ar²-M reagent (M=Li or MgX), which may beprepared for example from the corresponding suitably substitutedaromatic ring by metal-halide exchange, using for example nBuLi oriPrMgCl, under inert atmosphere like for example nitrogen atmosphere, atcontrolled temperature like for example −78° C., in a non protic solventlike for example dry THF (step i). Intermediates 2 may be furtherdehydrated to form intermediates 3, under acidic condition like forexample TFA neat or in the presence of DCM, at room temperature or underreflux (step ii).

The cycloalkenyl ketone intermediates 3 may be converted to thecorresponding cycloalkyl ketone intermediates 4 by a hydrogenolysisusing catalytic palladium like for example Pd/C, under hydrogenatmosphere, under pressure like for example 50 psi, at a temperaturelike for example 30° C. (step iii).

Ketone intermediates 4 may further react with POCl₃ in the presence ofDMF to provide the chloro-carbonyl intermediates 5 (step iv), which isengaged in a carbonylative coupling reaction using a CO-releaser reagentlike for example carbon monoxide, in the presence of a base such as Et₃Nor AcONa, and a transition metal catalyst such as Pd(dppf)Cl₂, or usingthe combination of a catalyst such as Pd(OAc)₂ and a ligand such asdppf, in a solvent like for example MeOH, at the appropriate temperatureto provide lactone intermediates 6 (step v).

According to Method A in scheme 1, intermediates 6 may react with anaryl or heteroaryl hydrazines Ar¹—NH₂—NH₂, which may be commerciallyavailable or prepared by a person skilled in the art of organicchemistry, in the presence of a catalyst such as PTSA, and a solventlike for example toluene or EtOH, at an appropriate temperature (stepix), to provide final compounds of Formula (I), (II) and (III) wherein Yis CH and R⁴, R⁸ and R⁹ are hydrogen.

Alternatively, according to Method B in scheme 1, intermediates 6 mayreact with hydrazine NH₂NH₂ in acidic condition, using either AcOH inthe presence of a solvent like EtOH, or PTSA in the presence of asolvent like toluene, at the appropriate temperature (step vii), toprovide intermediates 7. A cross-coupling reaction between intermediates7 and (hetero)aromatic halides Ar¹—X (preferably Ar¹—Br) in the presenceof a catalyst/ligand system like for example Pd₂(dba)₃/Xantphos, a baselike t-BuOK, in a solvent like toluene, or alternatively acopper-mediated coupling reaction using CuI, a ligand such as DMEDA orin a cyclic diamine ligand, in the presence of a base like K₃PO₄, and asolvent like DMF or a mixture of solvents like DMF/dioxane, at theappropriate temperature (step viii), to provide final compounds ofFormula (I), (II) and (III) wherein Y is CH and R⁴, R⁸ and R⁹ arehydrogen.

Alternatively, intermediates 7 can be engaged in a Chan-Lam couplingreaction using a boronic acid or ester Ar¹—B(OR′)₂, in the presence of acatalyst like for example Cu(OAc)₂, a base like for example pyridine, ina solvent like for example CH₂Cl₂, at an appropriate temperature (stepix), to provide final compounds of Formula (I), (II) and (III) wherein Yis CH and R⁴, R⁸ and R⁹ are hydrogen.

Alternatively, according to Method C in scheme 1, lactone intermediates6 can be converted in ester intermediates 8 using aqueous NaOH, followedby alkylation using an halo-alkyl reagent for example ethyl iodide, inthe presence of DMF at the appropriate temperature (step x).Intermediates 8 may then be engaged in a 1- or 2-step sequence,according to step xi followed by steps viii or ix, or according to stepxii, as per described in Method A and B, to provide final compounds ofFormula (I), (II) and (III) wherein Y is CH and R⁴ and R⁸ are hydrogen.

Compounds of Formula (I), (II) and (III) wherein R⁹ is hydrogen, mayalso be obtained according to Scheme 2 below:

Cyclic keto-acetal intermediates 9 may react with POCl₃ in the presenceof DMF to provide chloro-carbonyl intermediates 10 (step i).Intermediates 10 is engaged in a carbonylative coupling reaction using aCO-releaser reagent like for example carbon monoxide, in the presence ofa base such as Et₃N or AcONa, and a transition metal catalyst such asPd(dppf)Cl₂, or using the combination of a catalyst such as Pd(OAc)₂ anda ligand such as dppf, in a solvent like for example MeOH, at theappropriate temperature to provide ester-aldehyde intermediates 11 (stepii). Intermediates 12 may be obtained from the reaction of intermediates11 with hydrazine NH₂NH₂ in acidic condition, using either AcOH in thepresence of a solvent like EtOH, or PTSA in the presence of a solventlike toluene, at the appropriate temperature (step iii), followed by across-coupling reaction using an aromatic halide Ar¹—X (preferablyAr¹—Br) in the presence of a catalyst/ligand system like for examplePd₂(dba)₃/Xantphos, a base like t-BuOK, in a solvent like toluene, oralternatively a copper-mediated coupling reaction using CuI, a ligandsuch as DMEDA or in a cyclic diamine ligand, in the presence of a baselike K₃PO₄, and a solvent like DMF or a mixture of solvents likeDMF/dioxane, at the appropriate temperature (step iv).

Alternatively, intermediates 11 may react with an aryl hydrazineAr¹—NH₂—NH₂, which may be commercially available or prepared by a personskilled in the art of organic chemistry, in the presence of a catalystsuch as PTSA, and a solvent like for example toluene or EtOH, at anappropriate temperature to directly provide intermediates 13 (step v).

Intermediates 13 may be treated under acidic condition using aqueous TFAor HCl, in the presence of a solvent like acetonitrile or DCM, at theappropriate temperature to provide intermediates 14 (step vi). Ketoneintermediates 14 may react with Tf₂O in the presence of a base such asEt₃N and a solvent like DCM at the appropriate temperature to providekey triflate intermediates 15 (step vii).

According to Method A in scheme 2, intermediates 15 may be engaged in aSuzuki cross coupling reaction using a boronic ester Ar¹—B(OR′)₂ orboronic acid Ar¹—B(OH)₂ in the presence of a catalyst/ligand system likefor example Pd(PPh₃)₄, a base like Na₂CO₃, or K₂CO₃, in a solvent likeTHF or a mixture dioxane/H₂O, at the appropriate temperature to provideintermediates 16 (step viii).

Alternatively, according to Method B in scheme 2, intermediates 15 mayreact with bispinacol-diborane ester in the presence of a base such asNa₂CO₃, or K₂CO₃ and a catalytic system such as Pd(dppf)Cl₂, in asolvent like dioxane, at the appropriate temperature to provideintermediates 17 (step x). Intermediates 17 may be engaged in across-coupling reaction using an aromatic halide Ar²—X (preferablyAr^(e)—Br) in the presence of a catalyst/ligand system like for examplePd(dppf)Cl₂, a base like Na₂CO₃, in a solvent like dioxane-H₂O, at theappropriate temperature to provide intermediates 16 (step xi).

Finally, reduction of the cyclic double-bond in intermediates 16 may beperformed by hydrogenolysis using for example palladium hydroxide, inthe presence of ammonium formate, in a solvent like EtOH and at theappropriate a temperature, to provide final compounds of Formula (I),(II) and (III) wherein Y is CH and R² and R⁸ are hydrogen (step ix).

Compounds of Formula (I), (II) and (III) may also be obtained accordingto Scheme 3 below:

Cyclic enone intermediates 18 are commercially available or may besynthesized by a person skilled in the art of organic chemistry usingmultiple ways described in the literature. The may be engaged in across-coupling reaction using a boronic ester Ar¹—B(OR′)₂ or boronicacid Ar¹—B(OH)₂ in the presence of a catalyst/ligand system like forexample Rh(COD)Cl₂, a base like KOH, in a solvent like dioxane/H₂O, atthe appropriate temperature under inert atmosphere to provideintermediates 19 (step i). Ketone intermediates 19 may react with POCl₃in the presence of DMF to provide intermediates 20 (step ii), which inturn be engaged in a carbonylative coupling reaction using a CO-releaseragent like for example carbon monoxide, in the presence of a base suchas ET₃N or AcONa, and a transition metal catalyst such as Pd(dppf)Cl₂,in a solvent like for example EtOH, at the appropriate temperature toprovide ester-aldehyde intermediates 21 (step iii). Intermediates 21 mayreact with an (hetero)aryl hydrazine Ar¹—NH₂—NH₂, which may becommercially available or prepared by a person skilled in the art oforganic chemistry, in the presence of a catalyst such as PTSA, and asolvent like for example toluene or EtOH, at an appropriate temperature(step iv), to provide final compounds of Formula (I), (II) and (III)wherein Y is CH and R², R⁸ and R⁹ are hydrogen.

Compounds of Formula (I), (II) and (III) wherein R⁹ is hydrogen, mayalso be obtained according to Scheme 4 below:

Cycloalkylene ketone intermediates 18 are commercially available or maybe synthesized by a person skilled in the art of organic chemistry usingmultiple ways described in the literature. Intermediates 31 may beprepared by reacting intermediates 18 with a suitably substitutedaromatic halide Ar²—X (preferably Ar²—Br or Ar²—I) in a cross-couplingreaction in the presence of a transition metal catalyst like for examplePd(dppf)Cl₂, in a solvent like Et₃N or Na₂CO₃, in the presence of asolvent such as DMSO, at an appropriate temperature (step i).

Cycloalkenyl ketone intermediates 31 may be converted to thecorresponding keto-ester intermediates 34 by a two-step reactionsequence: (step ii) alpha-carboxylation using for examplecyanoethylcarbonate or diethylcarbonate, in the presence of a base likefor example LDA or NaH, in an aprotic solvent like for example THF, at acontrolled temperature like for example −78° C.; followed by (step iii)the double-bond hydrogenolysis using catalytic palladium like forexample Pd/C, under hydrogen atmosphere, under pressure like for example50 psi, at the appropriate temperature.

This 2-step sequence may be reverted starting first by thehydrogenolysis step (iii), followed by the alpha-carboxylation step (ii)using the aforementioned conditions, to provide keto-ester intermediates34.

Keto-ester intermediates 34 may react with formamidine in the presenceof a base such as K₂CO₃ and a solvent like EtOH at the appropriate atemperature to provide intermediates 35 (step iv).

Intermediates 35 may be engaged in a cross-coupling reaction asdescribed in Scheme 1, for example reacting with an aromatic halideAr¹—X (preferably Ar¹—Br) in the presence of a catalyst/ligand systemlike for example Pd₂(dba)₃/Xantphos, a base like t-BuOK, in a solventlike toluene, or alternatively a copper-mediated coupling reaction usingCuI, a ligand such as DMEDA or in a cyclic diamine ligand, in thepresence of a base like K₃PO₄, and a solvent like DMF or a mixture ofsolvents like DMF/dioxane, at the appropriate temperature (step v), toprovide final compounds of Formula (I), (II) and (III) wherein R², R⁷and R⁹ are hydrogen.

Any compounds of Formula (I), (II) or (III) wherein Ar² is substitutedby an OR group, may be obtained according to Scheme 5 below:

Compounds of Formula (I), (II) and (III), represented by intermediates49 wherein substituent B on Ar² is a methoxy group, may react with adealkylating agent such as boron tribromide in a solvent like DCM at theappropriate temperature (step i) to provide hydroxy intermediates 50.The hydroxy function may then react with an alkylating agent such asalkyl halide (e.g. R²—I, R²—Br or R²—Cl) in the presence of a base likeCs₂CO₃ in a solvent like DMF at the appropriate temperature (step ii) toprovide compounds of Formula (I), (II) and (III), wherein Ar² issubstituted by an oxo group.

Any compounds of Formula (I) (II) and (III), wherein Ar¹ is substitutedby an alkyl, aryl, heteroaryl, amino or alkoxy radical, may be obtainedaccording to Scheme 6 below:

Intermediates 51, representing by but not limited to intermediates 7 inscheme 1 or 35 in scheme 4, may be engaged in a cross-coupling reactionusing a halo (hetero)aryl of formula A-Ar¹—X, in the presence of acatalyst/ligand system (e.g. Pd₂(dba)₃/Xantphos), a base (e.g. t-BuOK),in a solvent (e.g. toluene), at an appropriate temperature to provideintermediates 51 (step i). According to Method A, intermediates 52wherein A is a halide radical Cl, Br or I, may further react withboronic acid or boronic esters in the presence of a catalyst/ligandsystem like for example Pd(dppf)Cl₂, or RuPhos, a base like KOAc orCs₂CO₃, in a solvent like dioxane or dioxane-H₂O, at the appropriatetemperature (step ii) to provide compounds of Formula (I), (II) and(III), wherein Ar¹ is bearing an alkyl, aryl or heteroaryl radical.

According to Method B, similar halide intermediates 52 (wherein A is ahalide radical) may react with an amine R¹R²NH in the presence or not ofa catalyst/ligand system like for example Pd(dppf)Cl₂, or RuPhos, a baselike Na₂CO₃ or Cs₂CO₃, in a solvent like dioxane, at the appropriatetemperature (step iii) to provide compounds of Formula (I), (II) and(III), wherein Ar¹ is bearing an amino radical.

Furthermore, according to Method C, intermediates 52, wherein A is a —OHradical, may react with an alkyl halide (like R—I, R—Br or R—Cl) in thepresence of a base like Cs₂CO₃ in a solvent like DMF at the appropriatetemperature (step iv) to provide compounds of Formula (I), (II) and(III), wherein Ar¹ is bearing an alkoxy radical.

Alternatively, compounds of Formula (I), (II) and (III) wherein Ar² isbearing a carbonyl group may be obtained according to Scheme 7 below:

Intermediates 53 wherein X is Br may be engaged in a cross-couplingreaction using a tributyl tin ethoxyvinyl, in the presence of acatalyst/ligand system (e.g. Pd(PPh₃)₄, a base (e.g. t-BuOK), in asolvent (e.g. dioxane), at an appropriate temperature, followed byhydrolysis in acidic media, such as aqueous HCl, in a solvent like EtOH,to provide intermediates 54. Reduction of the cyclic double-bond inintermediates 54 may be performed by hydrogenolysis using for examplepalladium on charcoal, in the presence of ammonium formate, in a solventlike EtOH and at the appropriate a temperature (step ii) to providefinal compounds of Formula (I), (II) and (III) wherein Y is CH, and Ar²is bearing an acetyl group.

B. Experimental

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification. Specifically, the following abbreviationsmay be used in the examples and throughout the specification.

ACN (acetonotrinile) K₃PO₄ (potassium phosphate) AcOH (acetic acid)KOt-Bu (potassium tert-butoxide) Bn (benzyl) LCMS (Liquid ChromatographyMass Spectrum) Boc₂O (di-tert-butyl dicarbonate) LDA CDCl₃ (deuteratedchloroform) M (molar) CH₂Cl₂ (dichloromethane) MeOH (methanol) CO(carbon monoxide) mg (milligrams) Cu(OAc)₂ (Copper(II) acetate) MHz(megahertz) DIPEA min (minutes) DMEDA (N,N- μL(microliters)Dimethylethylenediamine) DMF (dimethylformamide) μmol (micromoles) DMA(dimethylacetamide) mL (milliliters) DMAP (Dimethylaminopyridine) mmol(millimoles) DMFDMA (N,N-Dimethylformamide M.p. (melting point) dimethylacetal) Dppf MTBE (1,1′-bis(diphenylphosphanyl)ferrocene) Et₃N(triethylamine) n-BuLi (n-butyl lithium) EtOAc (or EA: ethyl acetate)N₂H₄ (hydrazine) EtOH (ethanol) NaBH₃CN (sodium cyanoborohydride) g(grams) NaBH(OAc)₃ ¹H (proton) NaH (sodium hydride) H₂ (hydrogen) NaHCO₃(sodium hydrogenocarbonate) HATU (1- NalO₄ (sodium periodate)[Bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate) HCl (hydrochloric acid) NaOMe HPLC (High PressureLiquid Na₂SO₄ (sodium sulphate) Chromatography) Hz (Hertz) NH₄Cl Pd/C(palladium on charcoal) NMR (Nuclear Magnetic Reasonance) Pd₂(dba)₃(palladium TFA (trifluoroacetic acid) (II)dibenzylideneacetone)PdCl₂(dppf)₂ THF (tetrahydrofuran) (Bis(1,1′-bis(diphenylphosphanyl)ferrocene palladium (II) dichloride) PdCl₂(PPh₃)₂(Bis(triphenylphosphine) TLC (thin layer chromatography) palladium (II)dichloride PE (Petroleum ether) TMG (trimethylguanidine) POCl₃(Phosphorus trichloride) TsOH (Tosyl acid) PtO₂ (Platinum Oxide)Xantphos (4,5- Bis(diphenylphosphino)- 9,9-dimethylxanthene) RT(Retention Time) XPhos (2- Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) RUPHOS (2- MnO₂ (Manganese dioxide)Dicyclohexylphosphino-2′,6′- diisopropoxybiphenyl)

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Celsius). All reactions are conducted not under an inertatmosphere at room temperature unless otherwise noted.

Example 1:6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,was Prepared According to Scheme 1, Method A

Intermediate 2a: 8-(2,4-dimethyl-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol

According to Scheme 1 Step i: To a solution of1-bromo-2,4-dimethyl-benzene (20.00 g, 108.07 mmol, 1.00 eq) in THF (100mL) under N₂ atmosphere and cooled to −70° C., was added n-BuLi (2.5 M,45.39 mL, 1.05 eq) dropwise. The reaction mixture was stirred at −70° C.for 2 hr. Then a solution of 1,4-dioxa-spiro[4.5]decan-8-one (17.72 g,113.47 mmol, 1.05 eq) in THF (100 mL) was added dropwise at −70° C., thereaction mixture was stirred at −70° C. for 2 hr. The reaction mixturewas quenched by water (300 mL) and extracted with EtOAc (200 mL×2). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by flash column chromatography on silicagel(PE:EtOAc 10/1 to 5/1). Intermediate 2a (24.00 g, 86.00 mmol, 79.57%yield) was obtained as a light-yellow solid.

¹H NMR (DMSO-d₆; 400 MHz) δ 7.31-7.29 (m, 1H), 6.90-6.89 (m, 2H), 4.66(s, 1H), 3.87 (s, 4H), 2.49 (s, 3H), 2.21 (s, 3H), 2.00-1.94 (m, 4H),1.79-1.76 (m, 2H), 1.53-1.51 (m, 2H).

Intermediate 3a: 4-(2,4-Dimethyl-phenyl)-cyclohex-3-enone

According to Scheme 1 Step ii: A solution of intermediate 2a (10.00 g,38.12 mmol, 1.00 eq) in TFA (500.00 mL) was stirred at 15° C. for 1 hr,then the mixture was stirred and heated to 80° C. for 18 hr. The mixturewas concentrated in vacuo. The residue was quenched by saturated NaHCO₃solution and pH was adjusted to pH 7-8, extracted with EtOAc (200 mL×2).The organic layer was dried over Na₂SO₄ and concentrated in vacuo. Thecrude product was purified by column chromatography on silica gel(PE:EtOAc 10/1 to 5/1). The intermediate 3a (11.00 g, 54.92 mmol, 72.04%yield) was obtained as a light-yellow oil. ¹H NMR (CDCl₃; 400 MHz) δ7.06-6.97 (m, 4H), 6.23-6.18 (m, 1H), 3.95-3.91 (m, 1H), 2.57-2.53 (m,2H), 2.51 (s, 3H), 2.50-2.33 (m, 4H), 1.99-1.95 (m, 1H).

Intermediate 4a: 4-(2,4-dimethylphenyl)cyclohexan-1-one

According to Scheme 1 Step iii: To a solution intermediate 3a (10.00 g,49.93 mmol, 1.00 eq) in EtOAc (100.00 mL) was added Pd/C (2.00 g, 49.93mmol, 1.00 eq) under N₂ atmosphere. The suspension was degassed undervacuo and purged with H₂ several times. The mixture was stirred under H₂(50 psi) at 30° C. for 4 hours. The mixture was filtered and filtratewas concentrated in vacuo. The crude product intermediate 4a (10.00 g,49.43 mmol, 99.01% yield) was obtained and used directly in the nextstep as a brown solid. ¹H NMR (CDCl₃; 400 MHz) δ 7.12-7.02 (m, 3H),3.25-3.22 (m, 1H), 2.57-2.53 (m, 4H), 2.41 (s, 3H), 2.33 (s, 3H),2.16-2.15 (m, 2H), 1.96-1.94 (m, 2H).

Intermediate 5a:2-Chloro-5-(2,4-dimethyl-phenyl)-cyclohex-1-enecarbaldehyde

According to Scheme 1 Step iv: To a solution of intermediate 4a (13.01g, 177.96 mmol, 12.00 eq) in CH₂Cl₂ (10 mL) at 0° C. under N₂ atmospherewas added POCl₃ (6.82 g, 44.49 mmol, 3.00 eq) dropwise. After stirringat 10° C. for 1 hr, a solution of intermediate 1c (3.00 g, 14.83 mmol,1.00 eq) in CH₂Cl₂ (40 mL) was added dropwise. The mixture was stirredat 50° C. for 4 hr. The mixture was quenched by saturated NaHCO₃solution and pH adjusted to pH 7-8, extracted with CH₂Cl₂ (150 mL×2).The organic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography over silicagel(PE/EtOAc=10/1), the intermediate 5a (1.70 g, 6.83 mmol, 46.06% yield)was obtained as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 10.25 (s, 1H),7.09-6.95 (m, 3H), 3.03-2.73 (m, 4H), 2.32 (d, J=2.6 Hz, 6H), 2.23-2.06(m, 1H), 2.05-1.90 (m, 2H).

Intermediate 6a:5-(2,4-dimethylphenyl)-3-methoxy-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

According to Scheme 1 Step v: To a mixture of intermediate 5a (500.00mg, 2.01 mmol, 1.00 eq), Pd(dppf)Cl₂ (147.08 mg, 201.01 μmol, 0.10 eq),Et₃N (610.19 mg, 6.03 mmol, 3.00 eq) in MeOH (10.00 mL) under N₂atmosphere. The suspension was degassed under vacuum and purged with COseveral times. The mixture was stirred under CO atmosphere (1 MPa) at90° C. for 12 hours. The mixture was filtered and filtrate wasconcentrated in vacuo. The intermediate 6a (650.00 mg, crude) wasobtained as brown solid. ¹H NMR: (400 MHz, CDCl₃) δ 7.09-6.98 (m, 3H),5.67 (s, 1H), 3.60 (s, 3H), 3.19-3.05 (m, 1H), 2.70-2.59 (m, 1H),2.57-2.44 (m, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 2.06-1.95 (m, 1H),1.88-1.76 (m, 1H).

Example 1:6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one

According to Scheme 1, Method A, step vi: A mixture of intermediate 6a(200.00 mg, 734.38 μmol, 1.00 eq) and pyridin-2-yl-hydrazinehydrochloride (160.28 mg, 1.47 mmol, 2.00 eq) in toluene (10.00 mL) wasstirred and heated to 110° C. for 8 hours. The mixture was concentratedin vacuo. The residue was dissolved in EtOAc (100 mL) and water (100mL), extracted with EtOAc (100 mL×2). The organic layer was dried overNa₂SO₄ and concentrated in vacuo. The crude product was purified byprep-HPLC and Example 1 (30.00 mg, 90.52 μmol, 6.16% yield) was obtainedas a brown solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.67 (d, J=4.0 Hz, 1H),7.82-7.91 (m, 1H), 7.69-7.77 (m, 2H), 7.33-7.39 (m, 1H), 6.99-7.15 (m,3H), 3.09-321 (m, 1H), 2.99 (d, J=17.6 Hz, 1H), 2.76-2.86 (m, 1H),2.59-2.75 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.08-2.19 (m, 1H),1.80-1.95 (m, 1H).

Example 2:6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method A

Intermediate 6b:3-methoxy-5-(3-methoxyphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

According to Scheme 1 Step i to v: Intermediate 6b was preparedsimilarly to intermediate 6a in Example 1, starting from1-bromo-3-methoxybenzene, and was obtained with an overall yield of 19%as a brown liquid. m/z (M+H)⁺=275.1.

Example 2:6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 1, Method A, step vi: Example 2 was prepared as perExample 1 starting from intermediate 6b (800.00 mg, 832.35 μmol) andpyridin-2-yl-hydrazine hydrochloride (181.77 mg, 1.25 mmol) to provideExample 2 (8.20 mg, 24.60 μmol) as a yellow solid. (¹H-NMR (400 MHz,MeOD) δ 8.62-8.61 (m, 1H), 8.08-8.05 (m, 1H), 7.90 (s, 1H), 7.69-7.67(m, 1H), 7.62-7.56 (m, 1H), 7.29-7.27 (m, 1H), 6.94-6.90 (m, 2H),6.83-6.84 (1H), 3.07-2.86 (m, 4H), 2.68-2.57 (m, 1H), 1.99-1.96 (m, 1H),1.96-1.93 (m, 1H).

Example 3:6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method A

Intermediate 6c:3-methoxy-5-(4-methoxyphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

According to Scheme 1 Step I to v: Intermediate 6c was preparedsimilarly to intermediate 6a in Example 1, starting from1-bromo-4-methoxybenzene, and was obtained with an overall yield of 14%as a brown liquid. ¹H NMR (MeOD; 400 MHz) δ 7.22-7.20 (m, 2H), 6.91-6.87(m, 2H), 5.88 (s, 1H), 3.93-3.91 (m, 1H), 3.83-3.81 (m, 1H), 3.77-3.80(m, 3H), 2.95-2.85 (m, 1H), 2.64-2.59 (m, 1H), 2.31-2.42 (m, 3H),2.05-2.03 (m, 1H), 1.85-1.80 (m, 1H), 1.30-1.25 (m, 3H).

Example 3:6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 1, Method A, step vi: Example 3 was prepared as perExample 1 starting from intermediate 6c (200.00 mg, 693.63 μmol) andpyridin-2-yl-hydrazine hydrochloride (201.97 mg, 1.39 mmol) to provideExample 3 (26.00 mg, 77.99 μmol) as a green solid. (¹H-NMR (400 MHz,DMSO-d₆) δ 8.61-8.60 (m, 1H), 8.04-8.00 (m, 1H), 7.59-7.56 (m, 2H),7.30-7.23 (m, 2H), 6.93-6.90 (m, 2H), 3.70 (s, 3H), 2.92-2.73 (m, 5H),2.05-2.02 (m, 1H), 1.85-1.82 (m, 1H), 1.81-1.78 (m, 1H).

Example 4:(+6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-oneand Example 5:(+)-6-(2,4-dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one

The enantiomers constituting racemic Example 1 (400 mg) were separatedby preparative SFC to give (−)6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-oneExample 4 (72 mg, 18%) with an enantiomeric excess of 100%, and (+)6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-oneExample 5 (59 mg, 15%) with an enantiomeric excess of 99%, both asyellow solid.

Example 4: ¹H-NMR (400 MHz, CDCl₃) δ 8.67 (br.s., 1H), 7.82-7.91 (m,1H), 7.69-7.77 (m, 2H), 7.33-7.39 (m, 1H), 6.99-7.15 (m, 3H), 3.09-321(m, 1H), 2.99 (d, J=17.6 Hz, 1H), 2.76-2.86 (m, 1H), 2.59-2.75 (m, 2H),2.36 (s, 3H), 2.33 (s, 3H), 2.08-2.19 (m, 1H), 1.80-1.95 (m, 1H).

Example 5: ¹H-NMR (400 MHz, CDCl₃) δ 8.67 (br.s., 1H), 7.82-7.91 (m,1H), 7.69-7.77 (m, 2H), 7.33-7.39 (m, 1H), 6.99-7.15 (m, 3H), 3.09-321(m, 1H), 2.99 (d, J=17.6 Hz, 1H), 2.76-2.86 (m, 1H), 2.59-2.75 (m, 2H),2.36 (s, 3H), 2.33 (s, 3H), 2.08-2.19 (m, 1H), 1.80-1.95 (m, 1H).

Example 6:6-(2,4-dimethylphenyl)-2-(5-chlororopyridin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

Intermediate 7a:6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 1 Step vii: To a solution of intermediate 6a (1.2 g,4.19 mmol, 1 eq) in EtOH (10 mL) and AcOH (1 mL) was added N₂H₄.H₂O(427.66 mg, 8.37 mmol, 415.20 gt, 2.0 eq). The mixture was stirred at80° C. for 3 hr, then cooled to 0° C. The white solid formed wascollected after filtering. Intermediate 7a (830 mg, 3.26 mmol, 77.96%yield) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.74(s, 1H), 7.64 (s, 1H), 7.15-7.08 (m, 1H), 7.03-6.93 (m, 2H), 3.09-2.93(m, 1H), 2.74-2.57 (m, 3H), 2.47-2.37 (m, 1H), 2.28 (s, 3H), 2.24 (s,3H), 1.96-1.85 (m, 1H), 1.83-1.68 (m, 1H).

Example 6:6-(2,4-dimethylphenyl)-2-(6-chloropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 1 Step viii: To a solution of intermediate 7a(100.00 mg, 353.87 μmol, 1.00 eq) in DMF (5.00 mL) was added5-chloro-2-bromopyridine (204.30 mg, 1.06 mmol, 3.00 eq), DMEDA (18.72mg, 212.32 μmol, 22.82 μL, 0.60 eq), CuI (33.70 mg, 176.94 μmol, 0.50eq), K₃PO₄ (187.79 mg, 884.68 μmol, 2.50 eq) at 20° C. under N₂atmosphere. Then the mixture was heated to 110° C. and stirred for 12hours. The reaction was filtered and the filtrate was acidified to pH=5with aqueous 12 M HCl and filtered. The filtrate was purified byprep-HPLC to provide Example 6 (71.93 mg, 196.61 μmol, 55.56% yield asan off-yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.62 (d, J=2.3 Hz, 1H),7.87-7.82 (m, 1H), 7.78-7.73 (m, 2H), 7.14-7.09 (m, 1H), 7.08-7.04 (m,2H), 3.20-3.11 (m, 1H), 3.04-2.95 (m, 1H), 2.87-2.78 (m, 1H), 2.77-2.60(m, 2H), 2.34 (s, 3H), 2.33 (s, 3H), 2.20-2.11 (m, 1H), 1.95-1.83 (m,1H).

Example 7:2-(4-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 7 was prepared as per Example6, starting from intermediate 7a (150.00 mg, 530.81 μmol) and2-bromo-4-chloropyridine (306.45 mg, 1.59 mmol), to provide Example 7(178.10 mg, 484.85 μmol, 91.34% yield) as brown solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.49 (d, J=5.4 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.66 (s, 1H),7.29 (dd, J=1.8, 5.3 Hz, 1H), 7.05-7.00 (m, 1H), 6.99-6.94 (m, 2H),3.12-3.02 (m, 1H), 2.96-2.86 (m, 1H), 2.80-2.69 (m, 1H), 2.67-2.53 (m,2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.10-2.02 (m, 1H), 1.86-1.74 (m, 1H).

Example 8:2-(3-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 8 was prepared as per Example6, starting from intermediate 7a (200.00 mg, 707.74 μmol) and2-bromo-3-chloropyridine (408.59 mg, 2.12 mmol), to provide Example 8(24.40 mg, 66.69 μmol, 9.42% yield) as an off-yellow solid. ¹H-NMR (400MHz, CDCl₃) δ 8.58 (dd, J=1.6, 4.7 Hz, 1H), 7.95 (dd, J=1.5, 8.0 Hz,1H), 7.72 (s, 1H), 7.44 (dd, J=4.6, 8.0 Hz, 1H), 7.16-7.11 (m, 1H),7.10-7.04 (m, 2H), 3.17 (br s, 1H), 3.02 (br d, J=19.6 Hz, 1H),2.89-2.78 (m, 1H), 2.78-2.61 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H),2.20-2.10 (m, 1H), 1.91 (br s, 1H).

Example 9:6-(2,4-dimethylphenyl)-2-(6-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 9 was prepared as per Example6, starting from intermediate 7a (70.00 mg, 275.23 μmol) and2-bromo-6-fluoropyridine (145.31 mg, 825.69 μmol), to provide Example 9(32.00 mg, 91.59 μmol, 33% yield) as a yellow solid. (¹H-NMR (400 MHz,DMSO-d₆) δ 8.23-8.21 (m, 1H), 7.88 (s, 1H), 7.61-7.59 (m, 1H), 7.36-7.34(m, 1H), 7.16-7.13 (m, 1H), 7.02-7.00 (m, 2H).

Example 10:6-(2,4-dimethylphenyl)-2-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 10 was prepared as per Example6, starting from intermediate 7a (70.00 mg, 275.23 μmol) and2-bromo-5-fluoropyridine (145.31 mg, 825.69 μmol), to provide Example 10(32.00 mg, 91.59 μmol, 23% yield) as a yellow solid. (¹H-NMR (400 MHz,DMSO-d₆) δ 8.62-8.61 (m, 1H), 7.97-7.95 (m, 1H), 7.86 (s, 1H), 7.71-7.67(m, 1H), 7.16-7.14 (m, 1H), 7.02-7.00 (m, 2H), 3.10-3.07 (m, 1H),2.84-2.70 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.94-1.84 (m, 1H),1.83-1.81 (m, 1H).

Example 11:6-(2,4-dimethylphenyl)-2-(4-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 11 was prepared as per Example6, starting from intermediate 7a (60.00 mg, 235.91 μmol) and2-bromo-4-fluoropyridine (103.79 mg, 589.78 μmol), to provide Example 11(24.00 mg, 68.69 μmol, 29% yield) as a yellow solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.66 (s, 1H), 7.88 (s, 1H), 7.66-7.61 (m, 1H), 7.53-7.51 (m,1H), 7.16-7.14 (m, 1H), 7.03-7.00 (m, 2H), 3.08-3.01 (m, 1H), 2.84-2.58(m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.94-1.84 (m, 1H), 1.83-1.81 (m,1H).

Example 12:6-(2,4-dimethylphenyl)-2-(3-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 12 was prepared as per Example6, starting from intermediate 7a (90.00 mg, 353.87 μmol) and2-bromo-3-fluoropyridine (186.83 mg, 1.06 mmol), to provide Example 12(15.00 mg, 42.93 μmol, 12% yield) as a yellow solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.50-8.48 (m, 1H), 8.06-8.01 (m, 1H), 7.92 (s, 1H), 7.72-7.70(s, 1H), 7.17-7.14 (m, 1H), 7.02-7.00 (m, 2H), 3.11-3.05 (m, 1H),2.86-2.68 (m, 4H), 2.34 (s, 3H), 2.27 (s, 3H), 1.94-1.83 (m, 2H).

Example 13:6-(2,4-dimethylphenyl)-2-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 13 was prepared as per Example6, starting from intermediate 7a (70.00 mg, 275.23 μmol) and2-bromo-4-methoxypyrimidine (129.37 mg, 688.08 μmol, 84.56 μL), toprovide Example 13 (45.00 mg, 124.50 μmol, 45% yield) as a yellow solid.¹H-NMR (400 MHz, DMSO-d₆) δ 7.93-7.84 (m, 1H), 7.84 (s, 1H), 7.16-7.12(m, 2H), 7.02-7.00 (m, 2H), 6.96-6.94 (m, 1H), 3.83 (s, 3H), 3.10-3.07(m, 1H), 2.81-2.66 (m, 4H), 2.31 (s, 3H), 2.25 (s, 3H), 1.95-1.93 (m,1H), 1.83-1.80 (m, 1H).

Example 14:6-(2,4-dimethylphenyl)-2-(5-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 14 was prepared as per Example6, starting from intermediate 7a (70.00 mg, 275.23 μmol) and2-bromo-5-methoxypyrimidine (129.37 mg, 688.08 μmol), to provide Example14 (30.00 mg, 83.00 μmol, 30.16% yield) as a yellow solid. ¹H-NMR (400MHz, DMSO-d₆) δ 8.28-8.27 (m, 1H), 7.82 (s, 1H), 7.60-7.59 (m, 1H),7.58-7.57 (m, 1H), 7.16-7.13 (m, 1H), 7.02-7.00 (m, 2H), 3.91 (s, 3H),3.10-3.07 (m, 1H), 2.93-2.55 (m, 4H), 2.31 (s, 3H), 2.25 (s, 3H),1.93-1.90 (m, 1H), 1.84-1.80 (m, 1H).

Example 15:6-(2,4-dimethylphenyl)-2-(4-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 15 was prepared as per Example6, starting from intermediate 7a (70.00 mg, 275.23 μmol) and2-bromo-4-methoxypyrimidine (129.37 mg, 688.08 μmol), to provide Example15 (53.00 mg, 146.64 μmol, 53% yield) as a yellow solid. ¹H-NMR (400MHz, DMSO-d₆) δ 8.41-8.39 (m, 1H), 7.83 (s, 1H), 7.16-7.10 (m, 3H),7.02-7.00 (m, 1H), 3.89 (s, 3H), 3.07-3.02 (m, 1H), 2.78-2.66 (m, 4H),2.30 (s, 3H), 2.25 (s, 3H), 1.93-1.83 (m, 1H), 1.82-1.80 (m, 1H).

Example 16:6-(2,4-dimethylphenyl)-2-(3-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 16 was prepared as per Example6, starting from intermediate 7a (90.00 mg, 353.87 μmol) and2-bromo-3-methoxypyrimidine (166.34 mg, 884.68 μmol), to provide Example16 (17.00 mg, 47.03 μmol, 13% yield) as a yellow solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.15-8.13 (m, 1H), 7.81 (s, 1H), 7.72-7.70 (m, 1H), 7.57-7.55(m, 1H), 7.16-7.14 (m, 1H), 7.02-7.00 (m, 2H), 3.80 (s, 3H), 3.10-3.07(m, 1H), 2.82-2.67 (m, 4H), 2.31 (s, 3H), 2.25 (s, 3H), 1.92-1.81 (m,2H).

Example 17:6-(2,4-dimethylphenyl)-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 17 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and2-bromo-6-methylpyridine (146.10 mg, 849.30 μmol, 96.75 μL), to provideExample 17 (59.06 mg, 170.97 μmol, 60.39% yield) as an off-yellow solid.¹H-NMR (400 MHz, CDCl₃) δ 7.81-7.69 (m, 2H), 7.45 (d, J=7.9 Hz, 1H),7.24 (d, J=7.7 Hz, 1H), 7.12-7.08 (m, 1H), 7.07-7.02 (m, 2H), 3.19-3.08(m, 1H), 3.03-2.92 (m, 1H), 2.86-2.76 (m, 1H), 2.73-2.59 (m, 5H), 2.35(s, 3H), 2.32 (s, 3H), 2.12 (td, J=2.9, 10.4 Hz, 1H), 1.94-1.80 (m, 1H).

Example 18:6-(2,4-dimethylphenyl)-2-(5-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 18 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and2-bromo-5-methylpyridine (146.10 mg, 849.30 μmol), to provide Example 18(52.33 mg, 151.49 μmol, 53.51% yield) as an off-yellow solid. ¹H-NMR(400 MHz, CDCl₃) δ 8.49 (d, J=1.5 Hz, 1H), 7.73 (s, 1H), 7.71-7.66 (m,1H), 7.64-7.60 (m, 1H), 7.14-7.10 (m, 1H), 7.08-7.04 (m, 2H), 3.21-3.09(m, 1H), 3.06-2.94 (m, 1H), 2.87-2.77 (m, 1H), 2.76-2.60 (m, 2H), 2.43(s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.19-2.09 (m, 1H), 1.96-1.81 (m,1H).

Example 19:6-(2,4-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was prepared according to Scheme 1, Method B

According to Scheme 1 Step viii: Example 19 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and2-bromo-4-methylpyridine (146.10 mg, 849.30 μmol, 94.26 μL), to provideExample 19 (69.51 mg, 201.22 μmol, 71.08% yield) as a white solid.¹H-NMR (400 MHz, CDCl₃) δ 8.53 (d, J=5.1 Hz, 1H), 7.74 (s, 1H), 7.56 (s,1H), 7.14-7.10 (m, 1H), 7.08-7.04 (m, 1H), 7.08-7.04 (m, 2H), 3.22-3.07(m, 1H), 3.06-2.95 (m, 1H), 2.87-2.78 (m, 1H), 2.76-2.61 (m, 2H), 2.47(s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.20-2.09 (m, 1H), 1.97-1.80 (m,1H).

Example 20:6-(2,4-dimethylphenyl)-2-(3-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 20 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and2-bromo-3-methylpyridine (146.09 mg, 849.30 μmol), to provide Example 20(8.60 mg, 24.75 μmol, 8.74% yield) as off-yellow solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.55-8.44 (m, 1H), 7.74 (d, J=6.7 Hz, 1H), 7.71 (s, 1H), 7.36(dd, J=4.8, 7.7 Hz, 1H), 7.16-7.11 (m, 1H), 7.10-7.04 (m, 2H), 3.16 (brs, 1H), 3.07-2.94 (m, 1H), 2.88-2.78 (m, 1H), 2.77-2.61 (m, 2H), 2.38(s, 3H), 2.36-2.33 (m, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.20-2.09 (m,1H), 1.98-1.83 (m, 1H).

Example 21:6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)picolinonitrile,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 21 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and6-bromopicolinonitrile (155.43 mg, 849.30 μmol), to provide Example 21(53.43 mg, 146.31 μmol, 51.68% yield) as a white solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.05-7.99 (m, 2H), 7.81-7.75 (m, 2H), 7.13-7.10 (m, 1H),7.08-7.05 (m, 2H), 3.21-3.11 (m, 1H), 2.99 (br dd, J=5.3, 19.1 Hz, 1H),2.89-2.80 (m, 1H), 2.78-2.59 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H),2.20-2.11 (m, 1H), 1.96-1.82 (m, 1H).

Example 22:6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 22 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and6-bromonicotinonitrile (155.43 mg, 849.30 μmol), to provide Example 22(21.19 mg, 59.45 μmol, 21.00% yield) as a white solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.86 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.98-7.91 (m, 1H),7.73-7.67 (m, 1H), 6.98 (d, J=17.4 Hz, 3H), 3.13-3.01 (m, 1H), 2.97-2.85(m, 1H), 2.79-2.70 (m, 1H), 2.68-2.52 (m, 2H), 2.27 (s, 3H), 2.25 (s,3H), 2.11-2.02 (m, 1H), 1.87-1.74 (m, 1H).

Example 23:2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)isonicotinonitrile,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 23 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and2-bromoisonicotinonitrile (17.27 mg, 94.37 μmol), to provide Example 23(28.72 mg, 80.58 μmol, 28.46% yield) as a white solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.85 (d, J=4.4 Hz, 1H), 8.13 (s, 1H), 7.78 (s, 1H), 7.59 (dd,J=1.3, 5.0 Hz, 1H), 7.16-7.03 (m, 3H), 3.22-3.12 (m, 1H), 3.06-2.96 (m,1H), 2.89-2.80 (m, 1H), 2.79-2.62 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H),2.21-2.12 (m, 1H), 1.98-1.83 (m, 1H).

Example 24:2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 24 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and2-bromonicotinonitrile (155.43 mg, 849.30 μmol), to provide Example 24(8.80 mg, 24.69 μmol, 8.72% yield) as a white solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.88 (d, J=5.0 Hz, 1H), 8.20 (d, J=7.9 Hz, 1H), 7.75 (s, 1H),7.61-7.52 (m, 1H), 7.15-7.04 (m, 3H), 3.22-3.13 (m, 1H), 3.08-3.00 (m,1H), 2.88-2.79 (m, 1H), 2.78-2.64 (m, 2H), 2.38 (s, 3H), 2.34 (s, 3H),2.15 (br s, 1H), 1.99-1.83 (m, 1H).

Example 25:6-(2,4-dimethylphenyl)-2-(5-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 25 was prepared as per Example6, starting from intermediate 7a (100.00 mg, 353.87 μmol) and6-bromo-3-hydroxypyridine (184.72 mg, 1.06 mmol), to provide Example 25(42.10 mg, 115.12 μmol, 32.53% yield) as an off-white solid. ¹H-NMR (400MHz, CDCl₃) δ 8.74 (s, 1H), 8.24 (dd, J=1.8, 4.8 Hz, 1H), 7.87 (dd,J=1.6, 7.8 Hz, 1H), 7.19 (dd, J=4.8, 7.8 Hz, 1H), 7.15-7.11 (m, 1H),7.09-7.04 (m, 2H), 3.26-3.16 (m, 1H), 3.15-3.06 (m, 1H), 3.04-2.96 (m,1H), 2.92-2.80 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.24-2.14 (m, 1H),2.04-1.95 (m, 1H).

Example 26:6-(2,4-dimethylphenyl)-2-(4-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a solution of compound Example 15 (200.00 mg, 553.34 μmol, 1.00 eq)in CH₂Cl₂ (5.00 mL) was added BBr₃ (693.11 mg, 2.77 mmol, 266.58 μL,5.00 eq). The mixture was stirred at 40° C. for 12 hours and desiredproduct was detected. The mixture was added to water (30 mL), exertedwith ethyl acetate (30 mL×3). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure and the residue waspurified by prep-TLC (PE:EtOAc=0:1). Example 26 (130.00 mg, 370.46 μmol,66.95% yield) was obtained as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ8.26 (br d, J=4.5 Hz, 1H), 7.81 (s, 1H), 7.15 (br d, J=7.9 Hz, 1H),7.05-6.96 (m, 2H), 6.86 (br s, 2H), 3.07 (br s, 1H), 2.85-2.59 (m, 3H),2.58-2.53 (m, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 1.93 (br s, 1H),1.88-1.75 (m, 1H).

Example 27:6-(2,4-dimethylphenyl)-2-(5-(methoxymethyl)pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 27 was prepared as per Example6, starting from intermediate 7a (100.00 mg, 353.87 μmol) and2-bromo-5-(methoxymethyl)pyridine (214.50 mg, 1.06 mmol), to provideExample 27 (56.21 mg, 149.71 μmol, 42.31% yield) as a white solid.¹H-NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 8.24 (dd, J=1.8, 4.8 Hz, 1H),7.87 (dd, J=1.6, 7.8 Hz, 1H), 7.19 (dd, J=4.8, 7.8 Hz, 1H), 7.15-7.11(m, 1H), 7.09-7.04 (m, 2H), 3.26-3.16 (m, 1H), 3.15-3.06 (m, 1H),3.04-2.96 (m, 1H), 2.92-2.80 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H),2.24-2.14 (m, 1H), 2.04-1.95 (m, 1H).

Example 28:6-(2,4-dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 28 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and3-bromopyridine (134.19 mg, 849.30 μmol, 81.82 μL), to provide Example28 (32.83 mg, 99.06 μmol, 34.99% yield) as a white solid. ¹H-NMR (400MHz, CDCl₃) δ 9.04-8.91 (m, 1H), 8.63 (br s, 1H), 8.09 (br d, J=8.3 Hz,1H), 7.73 (d, J=1.9 Hz, 1H), 7.44 (br s, 1H), 7.18-7.01 (m, 3H), 3.16(br s, 1H), 3.02 (br d, J=19.2 Hz, 1H), 2.88-2.79 (m, 1H), 2.77-2.61 (m,2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.17 (br d, J=13.1 Hz, 1H), 1.91 (br d,J=11.8 Hz, 1H).

Example 29:6-(2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 29 was prepared as per Example6, starting from intermediate 7a (780 mg, 3.07 mmol) and2-bromopyrimidine (585.11 mg, 3.68 mmol), to provide Example 29 (383.35mg, 1.12 mmol, 36.48% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ8.95 (d, J=4.9 Hz, 2H), 7.71 (s, 1H), 7.44 (t, J=4.8 Hz, 1H), 7.14-7.10(m, 1H), 7.08-7.04 (m, 2H), 3.21-3.11 (m, 1H), 3.08-2.98 (m, 1H),2.87-2.78 (m, 1H), 2.76-2.63 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 2.14(br dd, J=5.8, 13.5 Hz, 1H), 1.95-1.83 (m, 1H).

Example 30:6-(2,4-dimethylphenyl)-2-(pyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 30 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and2-bromopyrazine (135.02 mg, 849.30 μmol), to provide Example 30 (48.17mg, 144.92 μmol, 51.19% yield) as an off-yellow solid. ¹H-NMR (400 MHz,CDCl₃) δ 9.05 (d, J=1.1 Hz, 1H), 8.60-8.50 (m, 1H), 7.69 (s, 1H),7.05-7.01 (m, 1H), 7.00-6.94 (m, 2H), 3.13-3.02 (m, 1H), 3.13-3.02 (m,1H), 2.98-2.87 (m, 1H), 2.80-2.71 (m, 1H), 2.69-2.54 (m, 2H), 2.28 (s,3H), 2.25 (s, 3H), 2.12-2.02 (m, 1H), 1.88-1.74 (m, 1H).

Example 31:6-(2,4-dimethylphenyl)-2-(pyrimidin-5-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 31 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 283.10 μmol) and5-bromopyrimidine (135.02 mg, 849.30 μmol), to provide Example 31 (24.80mg, 74.61 μmol, 26.35% yield) as a brown solid. ¹H-NMR (400 MHz, CDCl₃)δ 9.23 (s, 2H), 9.19 (s, 1H), 7.74 (s, 1H), 7.12-7.08 (m, 1H), 7.08-7.03(m, 2H), 3.20-3.10 (m, 1H), 3.06-2.95 (m, 1H), 2.87-2.77 (m, 1H),2.76-2.60 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.21-2.11 (m, 1H),1.95-1.82 (m, 1H).

Example 32:6-(2,4-dimethylphenyl)-2-(thiazol-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was prepared according to Scheme 1, Method B

According to Scheme 1 Step viii: Example 32 was prepared as per Example6, starting from intermediate 7a (120.00 mg, 471.83 μmol) and2-bromothiazole (116.08 mg, 707.75 μmol, 63.78 μL), to provide Example32 (12.00 mg, 34.51 μmol, 8.76% yield) as a yellow solid. ¹H-NMR (400MHz, CDCl₃) δ 1.84-1.96 (m, 1H) 2.12-2.21 (m, 1H) 2.33 (s, 3H) 2.36 (s,3H) 2.66-2.81 (m, 2H) 2.82-2.92 (m, 1H) 3.07 (br dd, J=19.89, 5.08 Hz,1H) 3.12-3.20 (m, 1H) 7.05 (br d, J=5.77 Hz, 2H) 7.07-7.12 (m, 1H) 7.30(d, J=3.39 Hz, 1H) 7.81 (d, J=3.39 Hz, 1H) 7.90 (s, 1H).

Example 33:6-(2,4-dimethylphenyl)-2-(thiazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 33 was prepared as per Example6, starting from intermediate 7a (80.00 mg, 314.55 umol) and4-bromothiazole (77.39 mg, 471.83 μmol, 42.52 μL), to provide Example 33(8.00 mg, 23.44 μmol, 7.45% yield) as an off-white solid. ¹H-NMR (400MHz, CDCl₃) δ 7.89 (s, 1H), 7.65 (s, 2H), 7.14 (d, J=8.4 Hz, 1H),7.06-6.96 (m, 2H), 3.82 (s, 3H), 3.23-3.11 (m, 1H), 2.97-2.82 (m, 2H),2.81-2.71 (m, 1H), 2.70-2.57 (m, 1H), 2.36 (s, 3H), 2.29 (s, 3H),2.14-2.04 (m, 1H), 1.98-1.83 (m, 1H).

Example 34:6-(2,4-dimethylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 34 was prepared as per Example6, starting from intermediate 7a (100.00 mg, 353.87 μmol) and4-bromo-1-methyl-1H-imidazole (113.95 mg, 707.74 μmol), to provideExample 34 (10.61 mg, 31.72 μmol, 8.97% yield) as a white solid. ¹H-NMR(400 MHz, MeOD) δ 7.89 (s, 1H), 7.65 (s, 2H), 7.14 (d, J=8.4 Hz, 1H),7.06-6.96 (m, 2H), 3.82 (s, 3H), 3.23-3.11 (m, 1H), 2.97-2.82 (m, 2H),2.81-2.71 (m, 1H), 2.70-2.57 (m, 1H), 2.36 (s, 3H), 2.29 (s, 3H),2.14-2.04 (m, 1H), 1.98-1.83 (m, 1H)

Example 35:6-(2,4-dimethylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 35 was prepared as per Example6, starting from intermediate 7a (0.2 g, 786.39 μmol) and2-chloro-4-methoxypyrimidine (136.42 mg, 943.67 μmol), to provideExample 35 (0.118 g, 323.05 μmol, 41.08% yield) as white solid. ¹H-NMR(400 MHz, CDCl₃) δ 8.60 (s, 1H), 7.74 (s, 1H), 7.15-7.00 (m, 3H), 6.87(d, J=5.6 Hz, 1H), 4.06 (s, 3H), 3.21-3.10 (m, 1H), 3.09-3.01 (m, 1H),2.88-2.79 (m, 1H), 2.77-2.61 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H),2.18-2.10 (m, 1H), 1.95-1.81 (m, 1H).

Example 36:6-(2,4-dimethylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 36 was prepared as per Example6, starting from intermediate 7a (0.2 g, 786.39 μmol) and2-chloro-4,6-dimethylpyrimidine (168.19 mg, 1.18 mmol), to provideExample 36 (0.034 g, 89.61 μmol, 11.40% yield) as white solid. ¹H-NMR(400 MHz, CDCl₃) δ 7.69 (s, 1H), 7.15 (s, 1H), 7.12-7.07 (m, 1H),7.06-7.02 (m, 2H), 3.18-3.07 (m, 1H), 2.98-2.90 (m, 1H), 2.85-2.76 (m,1H), 2.74-2.65 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.16-2.05 (m, 1H),1.92-1.78 (m, 1H).

Example 37:2-(4-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 37 was prepared as per Example6, starting from intermediate 7a (0.2 g, 786.39 μmol) and2-chloro-4-cyclopropylpyrimidine (145.89 mg, 943.67 μmol), to provideExample 37 (0.029 g, 77.86 μmol, 9.90% yield) was obtained as a whitesolid. ¹H-NMR (400 MHz, CDCl₃) δ 8.64 (d, J=4.4 Hz, 1H), 7.65 (s, 1H),7.18 (d, J=4.8 Hz, 1H), 7.13-7.07 (m, 1H), 7.06-6.97 (m, 2H), 3.14-3.11(m, 1H), 3.04-2.92 (m, 1H), 2.84-2.74 (m, 1H), 2.69-2.63 (m, 2H), 2.35(s, 3H), 2.32 (s, 3H), 2.15-2.08 (m, 2H), 1.92-1.85 (m, 1H), 1.28-1.12(m, 4H).

Example 38:2-(5-hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

Intermediate 6d:3-methoxy-5-(3-methoxy-2-methylphenyl)-4,5,6,7-tetrahydroiso-benzofuran-1(3H)-one

According to Scheme 1 Step i to v: Intermediate 6d was preparedsimilarly to intermediate 6a in Example 1, starting from1-bromo-3-methoxy-2-methylbenzene, and was obtained with an overallyield 15% as a brown liquid. m/z (M+H)⁺=289.1.

Intermediate 7b:6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 1 Step vii: Intermediate 7b was prepared similarlyto intermediate 7a in Example 6, starting from Intermediate 6d (21.30 g,73.87 mmol), to provide Intermediate 7b 15.30 g, 56.60 mmol, 76.62%yield) as white solid. ¹H NMR (400 MHz, DMSO-d6) δ 12.76 (br s, 1H),7.65 (s, 1H), 7.10-7.18 (m, 1H), 6.84 (t, J=8.72 Hz, 2H), 3.77 (s, 3H),3.10 (br s, 1H), 2.55-2.75 (m, 3H), 2.35-2.47 (m, 1H), 2.15 (s, 3H),1.90 (br s, 1H), 1.76 (dq, J=4.89, 11.84 Hz, 1H).

Example 38:2-(5-hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 1 Step viii: Example 38 was prepared as per Example6, starting from intermediate 7b (150.00 mg, 554.88 μmol) and6-bromo-3-hydroxypyridine (115.86 mg, 665.85 μmol), to provide Example38 (72.80 mg, 200.12 μmol, 36.07% yield) as white solid. ¹H-NMR (400MHz, DMSO-d₆) δ 10.40 (br s, 1H), 8.04-8.10 (m, 1H), 7.80 (s, 1H),7.29-7.36 (m, 2H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.65 Hz, 1H), 6.85 (d,J=8.16 Hz, 1H), 3.78 (s, 3H), 3.09-3.21 (m, 1H), 2.62-2.82 (m, 3H),2.52-2.59 (m, 1H), 2.17 (s, 3H), 1.89-2.01 (m, 1H), 1.74-1.87 (m, 1H).

Example 39:2-(5-(hydroxymethyl)pyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 39 was prepared as per Example6, starting from intermediate 7b (150.00 mg, 554.88 μmol) and(6-bromopyridin-3-yl)methanol (125.19 mg, 665.86 μmol), to provideExample 39 (81.97 mg, 216.96 μmol, 39.10% yield) as white solid. ¹H-NMR(400 MHz, DMSO-d₆) δ 8.52 (d, J=1.63 Hz, 1H), 7.92 (dd, J=2.20, 8.09 Hz,1H), 7.84 (s, 1H), 7.52 (d, J=8.16 Hz, 1H), 7.18 (t, J=7.97 Hz, 1H),6.89 (d, J=7.78 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 5.45 (t, J=5.71 Hz,1H), 4.62 (d, J=5.52 Hz, 2H), 3.78 (s, 3H), 3.12-3.22 (m, 1H), 2.64-2.86(m, 3H), 2.55 (br d, J=9.66 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H),1.78-1.89 (m, 1H).

Example 40:6-(3-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 40 was prepared as per Example6, starting from intermediate 7b (150.00 mg, 554.88 μmol) and5-bromopyrimidine (105.86 mg, 665.86 μmol), to provide Example 40 (45.56mg, 128.81 μmol, 23.21% yield) as a brown solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 9.02 (d, J=4.89 Hz, 2H), 7.85 (s, 1H), 7.71 (t, J=4.89 Hz,1H), 7.14-7.21 (m, 1H), 6.87 (dd, J=7.97, 17.63 Hz, 2H), 3.78 (s, 3H),3.14-3.24 (m, 1H), 2.78-2.87 (m, 1H), 2.66-2.77 (m, 2H), 2.56 (br d,J=10.04 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78-1.91 (m, 1H).

Example 41:6-(3-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 41 was prepared as per Example6, starting from intermediate 7b (150.00 mg, 554.88 μmol) and2-bromo-5-methylpyrimidine (116.51 mg, 665.86 μmol), to provide Example41 (75.16 mg, 206.05 μmol, 37.13% yield) as a white solid. ¹H-NMR (400MHz, DMSO-d₆) δ 8.84 (s, 2H), 7.83 (s, 1H), 7.14-7.23 (m, 1H), 6.87 (dd,J=7.91, 16.69 Hz, 2H), 3.78 (s, 3H), 3.13-3.23 (m, 1H), 2.64-2.87 (m,3H), 2.52-2.60 (m, 1H), 2.38 (s, 3H), 2.18 (s, 3H), 1.94 (br s, 1H),1.75-1.90 (m, 1H).

Example 42:6-(3-methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 42 was prepared as per Example6, starting from intermediate 7b (150.00 mg, 554.88 μmol) and2-bromo-4-methoxypyrimidine (125.85 mg, 665.85 μmol), to provide Example42 (97.29 mg, 256.84 μmol, 46.29% yield) as red solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.69 (d, J=5.77 Hz, 1H), 7.83 (s, 1H), 7.18 (t, J=7.97 Hz,1H), 7.13 (d, J=5.90 Hz, 1H), 6.89 (d, J=7.65 Hz, 1H), 6.85 (d, J=8.16Hz, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 3.13-3.24 (m, 1H), 2.64-2.86 (m,3H), 2.56 (br d, J=9.41 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H),1.78-1.90 (m, 1H).

Example 43:2-(5-chloropyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 43 was prepared as per Example6, starting from intermediate 7b (150.00 mg, 554.88 μmol) and2-bromo-5-chloropyrimidine (128.80 mg, 665.86 μmol), to provide Example43 (98.84 mg, 257.92 μmol, 46.48% yield) as a white solid. ¹H-NMR (400MHz, DMSO-d₆)) δ 9.16 (s, 2H), 7.87 (s, 1H), 7.15-7.20 (m, 1H), 6.89 (d,J=7.65 Hz, 1H), 6.85 (d, J=8.03 Hz, 1H), 3.78 (s, 3H), 3.12-3.24 (m,1H), 2.78-2.86 (m, 1H), 2.65-2.76 (m, 2H), 2.53-2.61 (m, 1H), 2.18 (s,3H), 1.91-2.00 (m, 1H), 1.76-1.90 (m, 1H).

Example 44:6-(3-methoxy-2-methylphenyl)-2-(5-methoxypyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 44 was prepared as per Example6, starting from intermediate 7b (150.00 mg, 554.88 μmol) and2-bromo-5-methoxypyrazine (125.85 mg, 665.86 μmol), to provide Example44 (111.11 mg, 290.09 μmol, 52.28% yield) as a white solid. ¹H-NMR (400MHz, DMSO-d₆) δ 8.47 (d, J=1.25 Hz, 1H), 8.35 (d, J=1.25 Hz, 1H), 7.89(s, 1H), 7.14-7.22 (m, 1H), 6.89 (d, J=7.65 Hz, 1H), 6.85 (d, J=8.16 Hz,1H), 3.99 (s, 3H), 3.78 (s, 3H), 3.10-3.22 (m, 1H), 2.64-2.86 (m, 3H),2.56 (br d, J=9.41 Hz, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.78-1.89 (m,1H).

Example 45:2-(5-hydroxypyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 45 was prepared as per Example6, starting from intermediate 7b (450 mg, 1.66 mmol) and2-bromo-5-hydroxypyrimidine (349.55 mg, 2.00 mmol), to provide Example45 (520 mg, 1.43 mmol, 85.72% yield) as a brown solid. ¹H-NMR (400 MHz,DMSO-d₆) δ 8.43 (s, 2H), 7.79 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d,J=7.78 Hz, 1H), 6.85 (d, J=8.28 Hz, 1H), 3.76-3.81 (m, 3H), 3.11-3.25(m, 1H), 2.67-2.84 (m, 3H), 2.55-2.60 (m, 1H), 2.18 (s, 3H), 1.93 (br s,1H), 1.76-1.89 (m, 1H).

Example 46:6-(3-methoxy-2-methylphenyl)-2-(4-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 46 was prepared as per Example6, starting from intermediate 7b (70 mg, 258.95 μmol) and4-(2-bromopyrimidin-4-yl)morpholine (75.85 mg, 310.74 μmol), to provideExample 46 (32.49 mg, 74.12 μmol, 28.62% yield) as off-white solid.¹H-NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=6.15 Hz, 1H), 7.77 (s, 1H),7.15-7.21 (m, 1H), 6.96 (d, J=6.27 Hz, 1H), 6.89 (d, J=7.78 Hz, 1H),6.85 (d, J=8.16 Hz, 1H), 3.79 (s, 3H), 3.67 (br d, J=5.02 Hz, 4H), 3.62(br d, J=4.77 Hz, 4H), 3.17 (br t, J=8.97 Hz, 1H), 2.62-2.83 (m, 3H),2.52-2.59 (m, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.83 (dq, J=4.83,11.90 Hz, 1H).

Example 47:6-(5-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

Intermediate 6e:3-methoxy-5-(5-methoxy-2-methylphenyl)-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

According to Scheme 1 Steps i to v: Intermediate 6e was preparedsimilarly to intermediate 6a in example 1, starting from2-bromo-4-methoxy-1-methylbenzene, and was obtained with an overallyield of 9.3% as a yellow solid. ¹H NMR: (CDCl₃, 400 MHz) δ 7.02 (d,J=8.4 Hz, 1H), 6.70-6.61 (m, 2H), 5.58 (s, 1H), 3.71 (s, 3H), 3.51 (s,3H), 3.05-2.90 (m, 1H), 2.47-2.36 (m, 2H), 2.31-2.14 (m, 5H), 1.94-1.86(m, 1H), 1.75-1.62 (m, 1H).

Intermediate 7c:6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 1 Step vii: Intermediate 7c was prepared similarlyto intermediate 7a in Example 6, starting from intermediate 6e (1.30 g,4.51 mmol) to provide intermediate 7c (0.4 g, 1.48 mmol, 32.82% yield)as white solid. ¹H NMR: (CDCl₃, 400 MHz) δ 7.55 (s, 1H), 7.09 (d, J=8.0Hz, 1H), 6.73-6.68 (m, 2H), 3.78 (s, 3H), 3.12-3.08 (m, 1H), 2.93-2.91(m, 1H), 2.74-2.71 (m, 1H), 2.65-2.58 (m, 2H), 2.28 (s, 3H), 2.13-2.09(m, 1H), 1.90-1.69 (m, 1H).

Example 47:6-(5-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

According to Scheme 1 Step viii: Example 47 was prepared as per Example6, starting from intermediate 7c (0.1 g, 369.92 μmol) and2-chloro-5-methylpyrimidine (142.67 mg, 1.11 mmol), to provide Example47 (0.005 g, 13.80 μmol, 3.73% yield) as yellow solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.75 (s, 2H), 7.70 (s, 1H), 7.12 (br d, J=8.4 Hz, 1H), 6.77 (s,1H), 6.72 (m, d, J=8.4 Hz, 1H), 3.80 (s, 3H), 3.17-2.96 (m, 2H),2.87-2.76 (m, 1H), 2.71-2.65 (m, 2H), 2.43 (s, 3H), 2.31 (s, 3H),2.15-2.11 (m, 1H), 1.90-1.85 (m, 1H).

Example 48:6-(5-methoxy-2-methylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 48 was prepared as per Example6, starting from intermediate 7c (0.1 g, 369.92 μmol) and2-chloro-5-methoxypyrimidine (160.43 mg, 1.11 mmol), to provide Example48 (0.003 g, 7.93 μmol, 2.14% yield) as white solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.46 (s, 2H), 7.59 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.73-6.64(m, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 3.04-2.97 (m, 2H), 2.71-2.46 (m,3H), 2.23 (s, 3H), 2.08 (m, 1H), 1.80 (m, 1H).

Example 49:2-(5-chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step viii: Example 49 was prepared as per Example6, starting from intermediate 7c (0.1 g, 369.92 μmol) and2-bromo-5-chloropyrimidine (214.66 mg, 1.11 mmol), to provide Example 49(0.011 g, 28.73 μmol, 7.77% yield) as white solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.85 (s, 2H), 7.69 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.76 (s,1H), 6.72 (dd, J=8.0, 2.4 Hz, 1H), 3.80 (s, 3H), 3.18-3.08 (m, 1H),3.07-2.97 (m, 1H), 2.86-2.76 (m, 1H), 2.71-2.65 (m, 2H), 2.31 (s, 3H),2.15 (m, 1H), 1.88-1.81 (m, 1H).

Example 50:6-(2,4-dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method B

According to Scheme 1 Step ix: To a mixture of intermediate 7a (150.00mg, 530.81 μmol, 1.00 eq), 4-pyridiyl boronic acid (130.49 mg, 1.06mmol, 2.00 eq) in dioxane (5.00 mL) was added DMAP (194.55 mg, 1.59mmol, 3.00 eq), pyridine (41.99 mg, 530.81 μmol, 42.84 μL, 1.00 eq) andCu(OAc)₂ (96.41 mg, 530.81 μmol, 1.00 eq). The mixture was heated to 90°C. and stirred for 12 hour. The reactant mixture was filtered, thefiltrate was acidified to pH=5 with 12 M HCl and filtered. The obtainedsolution was purified by pre-HPLC to give Example 50 (8.98 mg, 26.01μmol, 4.90% yield) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.76(br s, 2H), 7.97 (s, 1H), 7.78 (br s, 2H), 7.15 (d, J=8.5 Hz, 1H),7.04-6.98 (m, 2H), 3.13-3.01 (m, 1H), 2.86-2.73 (m, 2H), 2.71-2.64 (m,1H), 2.63-2.55 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 2.00-1.91 (m, 1H),1.88-1.75 (m, 1H).

Example 51:2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method C

Intermediate 6a′:5-formyl-2′,4′-dimethyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-carboxylicacid

A solution of intermediate 6a (6 g, 22.03 mmol, 1 eq) in MeOH (100 mL)was added NaOH (2.64 g, 66.09 mmol, 3 eq) in H₂O (40 mL), then stirredat 20° C. for 24 hours. The organic solvent was removed under reducedpressure. The residue was acidified to pH=3 by addition 2N HCl at 20°C., and then extracted with EtOAc (30 mL×3). The combined organic layerswere washed with brine to pH=7, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (PE/EtOAc=50/1, 1/1) to afford intermediate 6a′ (2 g,7.74 mmol, 35.14% yield) as a light-yellow oil. ¹H NMR (400 MHz, CDCl₃)δ 7.16-6.93 (m, 3H), 6.03 (s, 1H), 3.20-3.01 (m, 1H), 2.79-2.64 (m, 1H),2.56-2.42 (m, 2H), 2.36-2.31 (m, 7H), 2.04-1.96 (m, 1H), 1.90-1.73 (m,1H).

Intermediate 8a: Ethyl5-formyl-2′,4′-dimethyl-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-carboxylate

According the scheme 1, step x: To a solution of intermediate 6a′ (2 g,7.74 mmol, 1 eq) in DMF (20 mL) was added TMG (1.34 g, 11.61 mmol, 1.46mL, 1.5 eq) at 20° C. After addition, the mixture was stirred at thistemperature for half an hour. Ethyl iodide (3.02 g, 19.36 mmol, 1.55 mL,2.5 eq) was added at 20° C. and the resulting mixture was immediatelyheated at 45° C. for 14 hours. The solvent was removed under reducedpressure. The residue was dissolved in water (20 mL), and then adjustedpH=4 with 4N HCl and extracted with EtOAc (15 mL×3). The combinedorganic layers were washed with water (10 mL×2), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (PE/EtOAc=20/1, 1/1) to affordintermediate 8a (1.8 g, 6.29 mmol, 81.18% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 7.13-6.94 (m, 3H), 4.34 (q,J=7.2 Hz, 2H), 3.00-2.88 (m, 1H), 2.83-2.71 (m, 2H), 2.70-2.57 (m, 1H),2.31 (s, 6H), 2.25-2.13 (m, 1H), 1.99 (m, 1H), 1.87-1.72 (m, 1H), 1.38(t, J=7.2 Hz, 3H).

Example 51:(2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

According the scheme 1, step xii: To a mixture of intermediate 8a (53.08mg, 367.19 μmol, 1 eq) in EtOH (10 mL) and AcOH (5 mL) was added2-hydrazineyl-5-chloropyrimidine (105.15 mg, 367.19 μmol, 1 eq) in oneportion at 20° C. The mixture was stirred at 100° C. for 12 hours. Themixture was filtered and concentrated in vacuo. The residue was purifiedby prep-HPLC to afford Example 51 (0.009 g, 24.53 μmol, 6.68% yield) asa white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.86 (s, 2H), 7.69 (s, 1H),7.16-6.99 (m, 3H), 3.14 (m, 1H), 3.01 (m, 1H), 2.86-2.77 (m, 1H),2.75-2.60 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 2.12 (m, 1H), 1.93-1.82(m, 1H).

Example 52:6-(2,4-dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method C

According the scheme 1, step xii: Example 52 was prepared as per Example51, starting from intermediate 8a (105.15 mg, 367.19 μmol) and2-hydrazineyl-5-methylpyrimidine (45.58 mg, 367.19 μmol), to provideExample 52 (0.023 g, 66.39 μmol, 18.08% yield) as white solid. ¹H-NMR(400 MHz, CDCl₃) δ 8.74 (s, 2H), 7.68 (s, 1H), 7.16-6.99 (m, 3H), 3.14(m, 1H), 3.06-2.96 (m, 1H), 2.86-2.76 (m, 1H), 2.69 (m, 2H), 2.43 (s,3H), 2.36 (s, 3H), 2.32 (s, 3H), 2.16-2.08 (m, 1H), 1.93-1.81 (m, 1H).

Example 53:6-(2,4-dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method C

According the scheme 1, step xii: Example 53 was prepared as per Example51, starting from intermediate 8a (105.15 mg, 367.19 μmol) and2-hydrazineyl-5-methoxypyrimidine (51.46 mg, 367.19 μmol), to provideExample 53 (0.059 g, 161.16 μmol, 43.89% yield) as white solid. ¹H-NMR(400 MHz, CDCl₃) δ 8.53 (s, 2H), 7.67 (s, 1H), 7.15-6.97 (m, 3H), 4.00(s, 3H), 3.14 (br s, 1H), 2.99 (m, 1H), 2.85-2.76 (m, 1H), 2.74-2.59 (m,2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (m, 1H), 1.87 (m, 1H).

Example 54:6-(2,4-dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method C

According the scheme 1, step xii: Example 54 was prepared as per Example51, starting from intermediate 8a (105.15 mg, 367.19 μmol) and5-fluoro-2-hydrazineylpyrimidine (47.04 mg, 367.19 μmol), to provideExample 54 (0.077 g, 217.32 μmol, 59.18% yield) as white solid. ¹H-NMR(400 MHz, CDCl₃) δ 8.77 (s, 2H), 7.68 (s, 1H), 7.13-6.99 (m, 3H), 3.15(m, 1H), 3.00 (m, 1H), 2.87-2.77 (m, 1H), 2.70 (m, 2H), 2.36 (s, 3H),2.32 (s, 3H), 2.15-2.08 (m, 1H), 1.95-1.82 (m, 1H).

Example 55:6-(2,4-dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method C

According the scheme 1, step xii: Example 55 was prepared as per Example51, starting from intermediate 8a (105.15 mg, 367.19 μmol) and2-hydrazineyl-5-(trifluoromethyl)pyrimidine (65.40 mg, 367.19 μmol), toprovide Example 55 (0.023 g, 55.36 μmol, 15.08% yield) as white solid.¹H-NMR (400 MHz, CDCl₃) δ 9.08 (s, 2H), 7.65 (s, 1H), 7.08-6.96 (m, 3H),3.21-3.10 (m, 1H), 3.07-2.97 (m, 1H), 2.87-2.78 (m, 1H), 2.36 (s, 3H),2.33 (s, 3H), 2.14 (m, 1H), 1.95-1.83 (m, 1H).

Example 56:6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method C

Intermediate 56′:2-(5-bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According the scheme 1, step xii: Intermediate 56′ was prepared as perExample 51, starting from intermediate 8a (392.32 mg, 1.37 mmol) and5-bromo-2-hydrazineyl-4-methoxypyrimidine (0.3 g, 1.37 mmol), to provideintermediate 56′ (0.17 g, 385.21 μmol, 28.12% yield) as white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.71 (s, 1H), 7.66 (s, 1H), 7.14-6.99 (m, 3H),4.13 (s, 3H), 3.20-3.08 (m, 1H), 3.04-2.94 (m, 1H), 2.85-2.75 (m, 1H),2.75-2.65 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.19-2.09 (m, 1H),1.92-1.85 (m, 1H).

Example 56:6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a mixture of methylboronic acid (27.13 mg, 453.19 μmol) andintermediate 56′ (0.1 g, 226.59 μmol) in dioxane (10 mL) was addedPd(dppf)Cl₂ (16.58 mg, 22.66 μmol, 0.1 eq) and K₂CO₃ (93.95 mg, 679.78μmol, 3 eq) in one portion at 20° C. under N₂. The mixture was stirredat 100° C. for 12 hours. The mixture was filtered and concentrated underreduced pressure. The residue was purified by prep-HPLC to affordExample 56 (0.044 g, 116.27 μmol, 51.31% yield) as white solid. ¹H-NMR(400 MHz, CDCl₃) δ 8.71 (s, 1H), 7.66 (s, 1H), 7.14-6.99 (m, 3H), 4.13(s, 3H), 3.20-3.08 (m, 1H), 3.04-2.94 (m, 1H), 2.85-2.75 (m, 1H),2.75-2.65 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.19-2.09 (m, 1H),1.92-1.85 (m, 1H).

Example 57:6-(2,4-dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 1, Method C

According the scheme 1, step xii: Example 57 was prepared as per Example51, starting from intermediate 8a (105.15 mg, 367.19 μmol) and4-((2-hydrazineylpyrimidin-5-yl)methyl)morpholine (76.83 mg, 367.19μmol), to provide Example 57 (0.023 g, 53.30 μmol, 14.52% yield) aswhite solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.87 (s, 2H), 7.69 (s, 1H),7.17-6.98 (m, 3H), 3.78-3.70 (m, 4H), 3.60 (s, 2H), 3.15 (m, 1H), 3.01(m, 1H), 2.87-2.76 (m, 1H), 2.70 (m, 1H), 2.75-2.61 (m, 1H), 2.51 (m,4H), 2.36 (s, 3H), 2.32 (s, 3H), 2.11 (m, 1H), 1.95-1.81 (m, 1H).

Example 58:6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 10: 8-chloro-1,4-dioxaspiro[4.5]dec-7-ene-7-carbaldehyde

According to scheme 2, step i: To a solution of DMF (187.11 g, 2.56 mol,196.96 mL, 2.00 eq) in CH₂Cl₂ (2.00 L) was added POCl₃ (490.66 g, 3.20mol, 297.37 mL, 2.50 eq) dropwise at 0° C. The mixture was stirred at 0°C. for 2 h. Then 1,4-dioxaspiro[4.5]decan-8-one (200.00 g, 1.28 mol,1.00 eq) in CH₂Cl₂ (500.00 mL) was added to the mixture dropwise at 0°C. The reaction mixture was stirred at 0° C. for 2 h. The reactionmixture poured into saturated NaHCO₃ aqueous (2 L) and keep at pH>7 byadded solid NaHCO₃, extracted by CH₂Cl₂ (5 L×2), CH₂Cl₂ phase wasconcentrated. The obtained residue was purified by column chromatography(PE/EtOAc=20/1). Intermediate 56a (120.00 g, 506.34 mmol, 39.56% yield)was obtained as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 10.19-10.10 (m,1H), 4.05-3.94 (m, 4H), 2.91-2.75 (m, 2H), 2.57-2.42 (m, 2H), 1.99-1.83(m, 2H).

Intermediate 11: methyl7-formyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

According to scheme 2, step ii: To a solution of intermediate 10 (122.00g, 514.78 mmol, 1.00 eq) in MeOH (800.00 mL) and DMA (400.00 mL) wasadded Pd(OAc)₂ (17.34 g, 77.22 mmol, 0.15 eq), DPPF (42.81 g, 77.22mmol, 0.15 eq) and AcONa (84.45 g, 1.03 mol, 2.00 eq). The reaction wasstirred at 80° C. under CO (50 Psi) for 12 h. The reaction mixture wasfiltered and the filtrate was concentrated and the residue was pouredinto water (2000 mL×2), extracted by ethyl acetate (2000 mL×3). Thecombined organic layers were washed by saturated salt water (1000 ml×3)and then concentrated under reduced pressure. The residue was purifiedby column chromatography (PE:EtOAc=20:1 to 3:1). Intermediate 11 (78.50g, 329.64 mmol, 64.04% yield) was obtained as a yellow oil. ¹H NMR (400MHz, CDCl₃) δ 5.61 (d, J=1.1 Hz, 1H), 4.03-3.99 (m, 4H), 3.53 (s, 3H),2.62-2.53 (m, 1H), 2.49-2.40 (m, 3H), 1.85 (t, J=6.3 Hz, 2H).

Intermediate 12:7,8-dihydro-2H-spiro[phthalazine-6,2′-[1,3]dioxolan]-1(5H)-one

According to scheme 2, step iii: To a solution of intermediate 11 (78.50g, 329.64 mmol, 1.00 eq) in EtOH (750.00 mL) and AcOH (75.00 mL) wasadded N₂H₄.H₂O (33.68 g, 659.28 mmol, 32.70 mL, 2.00 eq). The mixturewas stirred at 80° C. for 12 hours. The reactant mixture wasconcentrated and adjusted to pH=7 with saturated NaHCO₃ aqueoussolution. Then it was extracted with CH₂Cl₂ (30.00 mL×3). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated.Intermediate 12 (66.00 g, 316.99 mmol, 96.16% yield) was obtained as ayellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (s, 1H), 3.93 (s, 4H), 2.72 (s, 2H),2.54 (br t, J=6.7 Hz, 2H), 1.80 (t, J=6.7 Hz, 2H).

Intermediate 13a:2-(pyridin-2-yl)-7,8-dihydro-2H-spirolphthalazine-6,2′-[1,3]dioxolan]-1(5H)-one

According to scheme 2, step v: To a solution of intermediate 12 (40.00g, 192.11 mmol, 1.00 eq) and 2-bromo pyridine (36.42 g, 230.53 mmol,21.94 mL, 1.20 eq) in dioxane (500.00 mL) was added CuI (7.32 g, 38.42mmol, 0.20 eq), (1S,2S)-N¹,N²-dimethylcyclohexane-1,2-diamine (5.47 g,38.42 mmol, 0.20 eq) and K₃PO₄ (101.95 g, 480.28 mmol, 2.50 eq). Themixture was stirred at 100° C. for 12 hours. The reaction was filteredand concentrated. The filter cake was washed by CH₂Cl₂ (200 mL×3). Theresidue was added water (2.0 L) and extracted with CH₂Cl₂ (1.0 L×3). Thecombined organic layer was dried over Na₂SO₄, filtered and concentrated.The residue was re-crystallized from MTBE (100 mL) at 20° C.Intermediate 13a (56.00 g, crude) was obtained as a gray solid. ¹H NMR(400 MHz, CDCl₃) δ 8.67 (br s, 1H), 7.92-7.79 (m, 1H), 7.68 (br s, 2H),7.35 (br s, 1H), 4.04 (s, 4H), 2.87 (br t, J=6.0 Hz, 2H), 2.81 (s, 2H),1.94 (br t, J=6.5 Hz, 2H).

Intermediate 14a:2-(pyridin-2-yl)-7,8-dihydrophthalazine-1,6(2H,5H)-dione

According to scheme 2, step vi: To a solution of intermediate 13a (25.00g, 87.63 mmol, 1.00 eq) in CH₂Cl₂ (250.00 mL) and TFA (75.00 mL) wasadded H₂O (3.16 g, 175.26 mmol, 3.16 mL, 2.00 eq). The mixture wasstirred at 20° C. for 12 hours. The reaction was poured into saturatedNaHCO₃ aqueous solution (500.0 mL) and extracted with CH₂Cl₂ (500.0mL×3). The combined organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,CH₂Cl₂:EtOAc=1:2 to 0:1). Intermediate 14a (8.80 g, 33.20 mmol, 37.88%yield) was obtained as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (dd,J=1.1, 4.9 Hz, 1H), 7.89 (dt, J=1.9, 7.7 Hz, 1H), 7.75 (s, 1H), 7.70 (d,J=8.0 Hz, 1H), 7.39 (ddd, J=0.9, 4.9, 7.4 Hz, 1H), 3.46 (s, 2H), 3.16(t, J=7.0 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H).

Intermediate 15a:1-oxo-2-(pyridin-2-yl)-1,2,7,8-tetrahydrophthalazin-6-yltrifluoromethane-sulfonate

According to scheme 2, step vii: To a solution of intermediate 14a (5.00g, 18.86 mmol, 1.00 eq) in CH₂Cl₂ (50.00 mL) was added Et₃N (2.29 g,22.63 mmol, 3.14 mL, 1.20 eq) and Tf₂O (5.85 g, 20.75 mmol, 3.42 mL,1.10 eq) at 0° C. The reaction was stirred for 12 hours at 20° C. Thereactant mixture was concentrated to give a residue. The residue waspurified by column chromatography (SiO₂, PE:EtOAc=5:1 to 1:1).Intermediate 15a (4.40 g, 11.43 mmol, 60.62% yield) was obtained asyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.68-8.63 (m, 1H), 7.88 (dt,J=1.9, 7.8 Hz, 1H), 7.78 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.38 (ddd,J=0.9, 4.9, 7.4 Hz, 1H), 6.36 (t, J=1.4 Hz, 1H), 3.18-3.10 (m, 2H),2.84-2.75 (m, 2H).

Intermediate 16a:6-(2-methoxyphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: A mixture of intermediate 15a (200.00mg, 518.07 μmol, 1.00 eq), (2-methoxyphenyl)-boronic acid (157.45 mg,1.04 mmol, 2.00 eq), Pd(PPh₃)₄ (119.73 mg, 103.61 μmol, 0.20 eq), Na₂CO₃(2 M, 1.17 mL, 4.50 eq) in THF (4.00 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 70° C. for 3 hoursunder N₂ atmosphere. The mixture was added water (20 mL), extracted withAcOEt (20 mL×3), the organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-TLC (PE:EtOAc=0:1) to give intermediate 16a (190.00 mg,crude) as a yellow oil.

Example 58:6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: A mixture of intermediate 16a (200.00mg, 283.67 μmol, 1.00 eq), Pd(OH)₂ (79.68 mg, 56.73 μmol, 10% purity,0.20 eq) and ammonium formate (178.88 mg, 2.84 mmol, 10.00 eq) in EtOH(20.00 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 60° C. for 2 hours under N₂ atmosphere. Themixture was filtered, concentrated under reduced pressure and purifiedby prep-HPLC to give Example 58 (27.59 mg, 82.68 μmol, 29.15% yield) asa white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.68 (dd, J=1.1, 4.8 Hz, 1H),7.88 (dt, J=1.9, 7.8 Hz, 1H), 7.78-7.72 (m, 2H), 7.37 (ddd, J=0.9, 4.9,7.3 Hz, 1H), 7.28-7.25 (m, 1H), 7.21 (dd, J=1.5, 7.5 Hz, 1H), 7.02-6.97(m, 1H), 6.94 (d, J=8.3 Hz, 1H), 3.88 (s, 3H), 3.45-3.31 (m, 1H),3.05-2.88 (m, 2H), 2.75-2.60 (m, 2H), 2.22-2.13 (m, 1H), 2.05-1.89 (m,1H).

Example 59:6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16b:6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16b was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (200.00 mg, 486.46 μmol) and(3-(dimethylamino)phenyl)boronic acid (160.53 mg, 972.92 μmol) to giveintermediate 16b (160.00 mg, 427.40 μmol, 87.86% yield) as a yellow oil.

Example 59:6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 59 was prepared following thesame procedure described for Example 58, starting from intermediate 16b(160.00 mg, 427.40 μmol) to yield Example 59 (15.47 mg, 43.85 μmol,10.26% yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.69 (dd,J=1.1, 4.8 Hz, 1H), 7.89 (dt, J=1.9, 7.8 Hz, 1H), 7.78-7.73 (m, 2H),7.38 (ddd, J=1.0, 4.9, 7.4 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.70-6.63(m, 3H), 3.05-2.98 (m, 1H), 3.05-2.98 (m, 7H), 2.96-2.86 (m, 2H),2.84-2.75 (m, 1H), 2.72-2.59 (m, 1H), 2.30-2.21 (m, 1H), 1.98-1.85 (m,1H).

Example 60:6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16c:6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16c was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (200.00 mg, 518.07 μmol) and(3-methoxy-2-methylphenyl)boronic acid (85.99 mg, 518.07 μmol) to giveintermediate 16c (200.00 mg, 272.16 μmol, 52.53% yield) as a yellow oil.

Example 60:6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 60 was prepared following thesame procedure described for Example 58, starting from intermediate 16c(170.00 mg, 492.20 μmol) to yield Example 60 (24.35 mg, 69.95 μmol,14.21% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.69 (dd, J=1.1,4.8 Hz, 1H), 7.89 (dt, J=1.9, 7.8 Hz, 1H), 7.79-7.71 (m, 2H), 7.38 (ddd,J=0.9, 4.9, 7.4 Hz, 1H), 7.26-7.18 (m, 1H), 6.91-6.78 (m, 2H), 3.87 (s,3H), 3.31-3.18 (m, 1H), 3.06-2.94 (m, 1H), 2.89-2.79 (m, 1H), 2.78-2.63(m, 2H), 2.27 (s, 3H), 2.20-2.12 (m, 1H), 1.98-1.85 (m, 1H).

Example 61:6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16d:6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16d was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (227.51 mg, 589.32 μmol) and(5-methoxy-2-methylphenyl)boronic acid (97.82 mg, 589.32 μmol) to giveintermediate 16d (200.00 mg, crude) as a yellow oil.

Example 61:6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 61 was prepared following thesame procedure described for Example 58, starting from intermediate 16d(200.00 mg, 579.06 μmol) to yield Example 61 (19.01 mg, 52.64 μmol,9.09% yield) was obtained as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ8.69 (dd, J=1.1, 4.8 Hz, 1H), 7.89 (dt, J=1.9, 7.8 Hz, 1H), 7.77-7.73(m, 2H), 7.38 (ddd, J=1.0, 4.9, 7.4 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H),6.80 (d, J=2.6 Hz, 1H), 6.74 (dd, J=2.6, 8.3 Hz, 1H), 3.82 (s, 3H),3.20-3.10 (m, 1H), 3.08-2.99 (m, 1H), 2.88-2.80 (m, 1H), 2.75-2.62 (m,2H), 2.33 (s, 3H), 2.22-2.13 (m, 1H), 1.95-1.83 (m, 1H).

Example 62:2-(pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, wasPrepared According to Scheme 2, Method A

Intermediate 16e:2-(pyridin-2-yl)-6-(o-tolyl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16e was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (200.00 mg, 486.46 μmol) ando-tolylboronic acid (132.28 mg, 972.92 μmol) to give intermediate 16e(70.00 mg, 210.86 μmol, 43.35% yield) as brown solid.

Example 62:2-(pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 62 was prepared following thesame procedure described for Example 58, starting from intermediate 16e(70.00 mg, 210.86 μmol) to yield Example 62 (12.55 mg, 39.07 μmol,18.53% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.59 (dd, J=1.1,4.8 Hz, 1H), 7.80 (dt, J=1.9, 7.7 Hz, 1H), 7.70-7.62 (m, 2H), 7.29 (ddd,J=0.9, 4.9, 7.5 Hz, 1H), 7.17-7.07 (m, 4H), 3.16-3.05 (m, 1H), 2.98-2.86(m, 1H), 2.81-2.71 (m, 1H), 2.69-2.53 (m, 2H), 2.32 (s, 3H), 2.13-2.03(m, 1H), 1.89-1.76 (m, 1H).

Example 63:6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16f:6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16f was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (100.00 mg, 243.23 μmol) and(3-cyclopropylphenyl)boronic acid pinacol ester (89.07 mg, 364.85 μmol)to give intermediate 16f (20.00 mg, 42.76 μmol, 17.58% yield) as a brownsolid.

Example 63:6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 63 was prepared following thesame procedure described for Example 58, starting from intermediate 16f(10.00 mg, 21.38 μmol) to yield Example 63 (4.63 mg, 13.48 μmol, 63.06%yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.68 (br d, J=3.8 Hz,1H), 7.94-7.84 (m, 1H), 7.79-7.71 (m, 2H), 7.42-7.34 (m, 1H), 7.31-7.23(m, 2H), 7.09-7.01 (m, 2H), 6.97 (br d, J=7.4 Hz, 1H), 3.05-2.84 (m,3H), 2.82-2.60 (m, 2H), 2.24 (br d, J=8.9 Hz, 1H), 1.98-1.83 (m, 2H),1.06-0.95 (m, 2H), 0.74 (q, J=4.9 Hz, 2H).

Example 64:6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16g:6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16g was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (200.00 mg, 518.07 μmol) and(3-methoxy-4-methylphenyl)boronic acid (171.98 mg, 1.04 mmol) to giveintermediate 16g (130.00 mg, 299.60 μmol, 57.83% yield) as a yellowsolid. m/z (M+H)⁺=346.1.

Example 64:6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 64 was prepared following thesame procedure described for Example 58, starting from intermediate 16g(130.00 mg, 299.60 μmol) to yield Example 64 (31.00 mg, 89.23 μmol,29.78% yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.62-8.56 (m,1H), 7.83-7.76 (m, 1H), 7.68-7.62 (m, 2H), 7.32-7.25 (m, 1H), 7.04 (d,J=7.5 Hz, 1H), 6.69 (d, J=7.5 Hz, 1H), 6.66 (s, 1H), 3.79 (s, 3H),2.96-2.76 (m, 3H), 2.74-2.49 (m, 2H), 2.21-2.10 (m, 4H), 1.88-1.73 (m,1H).

Example 65:6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16h:6-(3-acetylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16h was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (100.00 mg, 243.23 μmol) and(3-acetylphenyl)boronic acid (59.82 mg, 364.85 μmol) to giveintermediate 16h (70.00 mg, 156.97 μmol, 64.54% yield) as off-whitesolid. m/z (M+H)⁺=344.1.

Example 65:6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 65 was prepared following thesame procedure described for Example 58, starting from intermediate 16h(70.00 mg, 156.97 μmol) to yield Example 65 (4.05 mg, 11.54 μmol, 4.31%yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.68 (br d, J=3.9 Hz,1H), 7.93-7.85 (m, 1H), 7.79-7.70 (m, 2H), 7.41-7.35 (m, 2H), 7.32 (brd, J=7.9 Hz, 2H), 7.21 (br d, J=7.5 Hz, 1H), 4.95 (q, J=6.3 Hz, 1H),3.06-2.96 (m, 2H), 2.95-2.86 (m, 1H), 2.84-2.74 (m, 1H), 2.73-2.61 (m,1H), 2.26 (br d, J=9.0 Hz, 1H), 1.98-1.88 (m, 1H), 1.88-1.77 (m, 1H),1.55 (d, J=6.5 Hz, 3H).

Example 66:6-(3-cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16i:6-(3-cyclopropoxyphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16i was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (100.00 mg, 243.23 μmol) and(3-cyclopropoxyphenyl)boronic acid pinacol ester (96.85 mg, 364.84 μmol)to give intermediate 16i (80.00 mg, 118.63 μmol, 48.78% yield) as anoff-white solid. m/z (M+H)⁺=358.1.

Example 66:6-(3-cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 66 was prepared following thesame procedure described for Example 58, starting from intermediate 16i(40.00 mg, 59.32 μmol) to yield Example 66 (8.54 mg, 23.74 μmol, 40.01%yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.68 (br d, J=4.3 Hz,1H), 7.89 (dt, J=1.6, 7.7 Hz, 1H), 7.78-7.72 (m, 2H), 7.38 (dd, J=5.0,7.2 Hz, 1H), 7.34-7.29 (m, 1H), 7.01 (dd, J=2.0, 8.2 Hz, 1H), 6.94 (s,1H), 6.90 (d, J=7.7 Hz, 1H), 3.82-3.71 (m, 1H), 3.03-2.86 (m, 3H),2.82-2.59 (m, 2H), 2.25 (br d, J=13.2 Hz, 1H), 1.97-1.83 (m, 1H),0.84-0.79 (m, 4H).

Example 67:6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16j:6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16j was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (200.00 mg, 519.68 μmol) and(2-methoxy-4-methylphenyl)boronic acid (129.38 mg, 779.52 μmol) to giveintermediate 16j (180.00 mg, crude) as brown oil. m/z (M+H)⁺=346.1.

Example 67:6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 67 was prepared following thesame procedure described for Example 58, starting from intermediate 16j(180.00 mg, 521.15 μmol) to yield Example 67 (24.94 mg, 71.64 μmol,13.75% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.8Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.9 Hz, 1H), 7.08 (dt, J=1.4, 8.0 Hz,1H), 6.93-6.87 (m, 1H), 6.81 (t, J=6.5 Hz, 1H), 3.92 (s, 3H), 3.41-3.28(m, 1H), 3.04-2.88 (m, 2H), 2.81-2.63 (m, 2H), 2.24-2.14 (m, 1H),2.02-1.91 (m, 1H).

Example 68:6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16k:6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16k was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (200.00 mg, 519.68 μmol) and(2-methoxy-3-methylphenyl)boronic acid pinacol ester (214.90 mg, 779.51μmol) to give intermediate 16k (190.00 mg, crude) as a brown oil. m/z(M+H)⁺=346.1.

Example 68:6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 68 was prepared following thesame procedure described for Example 58, starting from intermediate 16k(190.00 mg, 550.10 μmol) to yield Example 68 (16.44 mg, 46.80 μmol,8.51% yield) as white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 2H),7.79 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.78 Hz, 1H), 6.85 (d,J=8.28 Hz, 1H), 3.76-3.81 (m, 3H), 3.11-3.25 (m, 1H), 2.67-2.84 (m, 3H),2.55-2.60 (m, 1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.76-1.89 (m, 1H).

Example 69:6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16l:6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16l was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15a (0.2 g, 535.75 μmol) and(1-methylindolin-4-yl)boronic acid pinacol ester (138.84 mg, 535.75μmol) to give intermediate 16l (0.15 g, crude) as yellow solid. m/z(M+H)⁺=357.3; ¹H NMR (MeOD, 400 MHz) δ 8.60 (br d, J=4.4 Hz, 1H),7.94-8.08 (m, 2H), 7.67 (br d, J=7.6 Hz, 1H), 7.46-7.56 (m, 1H), 7.13(br t, J=7.6 Hz, 1H), 6.77 (br d, J=8.0 Hz, 1H), 6.47-6.59 (m, 2H),3.04-3.14 (m, 2H), 2.87-2.97 (m, 2H), 2.79-2.86 (m, 2H), 2.76 (s, 3H).

Example 69:6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 69 was prepared following thesame procedure described for Example 58, starting from intermediate 16l(0.15 g, 420.85 μmol), to provide Example 69 (55 mg, 151.30 μmol, 35.95%yield) as white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.67 (br d, J=3.6 Hz,1H), 7.87 (td, J=7.8, 2.0 Hz, 1H), 7.71-7.78 (m, 2H), 7.36 (dd, J=6.4,5.0 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.42 (d,J=7.8 Hz, 1H), 3.29-3.41 (m, 2H), 2.89-3.11 (m, 4H), 2.75-2.88 (m, 5H),2.53-2.72 (m, 1H), 2.17 (m, 1H), 1.80-1.98 (m, 1H).

Example 70:6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 13b:2-(pyrimidin-2-yl)-7,8-dihydro-2H-spiro[phthalazine-6,2′-[1,3]dioxolan]-1(5H)-one

According to scheme 2, step iv: Intermediate 13b was prepared followingthe procedure described for intermediate 13a, starting from intermediate12 (40.00 g, 192.11 mmol) and 2-bromopyrimidine (36.65 g, 230.53 mmol),to provide intermediate 13b (62.00 g, crude) as a gray solid. ¹H NMR(400 MHz, CDCl₃) δ 8.92 (d, J=4.8 Hz, 2H), 7.63 (s, 1H), 7.40 (t, J=4.8Hz, 1H), 4.05 (s, 4H), 2.91 (br t, J=6.7 Hz, 2H), 2.81 (s, 2H), 1.94 (t,J=6.7 Hz, 2H).

Intermediate 14b:2-(pyrimidin-2-yl)-7,8-dihydrophthalazine-1,6(2H,5H)-dione

According to scheme 2, step vi: Intermediate 14b was prepared followinga similar procedure described for intermediate 14a, starting fromintermediate 13b (18.00 g, 62.87 mmol) to provide intermediate 14b (7.60g, 18.83 mmol, 29.95% yield) as brown solid. ¹H NMR (400 MHz, DMSO-d6) δ9.04 (d, J=4.8 Hz, 2H), 7.88 (s, 1H), 7.79 (d, J=6.4 Hz, 1H), 3.55 (s,2H), 2.95 (br t, J=6.9 Hz, 2H), 2.56 (t, J=7.0 Hz, 2H).

Intermediate 15b:1-oxo-2-(pyrimidin-2-yl)-1,2,7,8-tetrahydrophthalazin-6-yltrifluoromethane-sulfonate

According to scheme 2, step vii: Intermediate 15b was prepared followingthe procedure described for intermediate 15a, starting from intermediate14b (3.50 g, 14.45 mmol), to provide Intermediate 15b (4.30 g, 8.62mmol, 59.63% yield) as yellow solid. ¹H NMR (400 MHz, MeOD) δ 9.03-8.94(m, 2H), 8.03-7.92 (m, 1H), 7.70-7.59 (m, 1H), 6.66 (t, J=1.4 Hz, 1H),3.15-3.05 (m, 2H), 2.92-2.83 (m, 2H).

Intermediate 16m:6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16m was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15b (200.00 mg, 480.91 μmol) and(2-methoxy-4-methylphenyl)boronic acid (119.73 mg, 721.37 μmol) to giveintermediate 16m (177.00 mg, crude) as yellow oil. m/z (M+H)⁺=347.1.

Example 70:6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 70 was prepared following thesame procedure described for Example 58, starting from intermediate 16m(177.00 mg, 511.00 μmol) to provide Example 70 (23.80 mg, 62.85 μmol,12.30% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H),9.02 (s, 1H), 7.85 (s, 1H), 7.72 (t, J=4.89 Hz, 1H), 7.12-7.18 (m, 1H),6.88 (d, J=3.39 Hz, 1H), 6.86 (d, J=3.89 Hz, 1H), 4.43-4.71 (m, 1H),3.12-3.22 (m, 1H), 2.66-2.86 (m, 3H), 2.56 (br d, J=9.91 Hz, 1H), 2.18(s, 3H), 1.91-2.00 (m, 1H), 1.79-1.90 (m, 1H), 1.28 (d, J=6.02 Hz, 6H).

Example 71:6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16n:6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16n was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (200.00 mg, 480.90 μmol) and(2-methoxy-3-methylphenyl)boronic acid pinacol ester (198.88 mg, 721.35μmol) to provide Intermediate 16n (180.00 mg, crude) as a brown oil. m/z(M+H)⁺=347.1.

Example 71:6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 71 was prepared following thesame procedure described for Example 58, starting from intermediate 16n(180.00 mg, 519.66 μmol) to yield Example 71 (13.00 mg, 37.31 μmol,7.18% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H),9.02 (s, 1H), 7.86 (s, 1H), 7.72 (t, J=4.89 Hz, 1H), 7.12-7.20 (m, 1H),6.90 (d, J=7.65 Hz, 1H), 6.86 (d, J=8.03 Hz, 1H), 4.09 (dd, J=3.89, 5.40Hz, 2H), 3.66-3.74 (m, 2H), 3.12-3.23 (m, 1H), 2.65-2.88 (m, 3H), 2.57(br d, J=8.28 Hz, 1H), 2.20 (s, 3H), 1.95 (br s, 1H), 1.78-1.90 (m, 1H).

Example 72:6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16o:6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16o was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (200.00 mg, 480.91 μmol) and(2-chloro-3-methoxyphenyl)boronic acid pinacolester (134.46 mg, 721.37μmol) to provide intermediate 16o (190.00 mg, crude) as yellow oil. m/z(M+H)⁺=367.0, 369.0.

Example 72:6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 72 was prepared following thesame procedure described for Example 58, starting from intermediate 16o(190.00 mg, 517.99 μmol), to provide Example 72 (29.90 mg, 80.42 μmol,15.53% yield), as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.03 (s,1H), 9.01 (s, 1H), 7.85 (s, 1H), 7.71 (t, J=4.83 Hz, 1H), 7.45-7.51 (m,2H), 7.41 (t, J=7.40 Hz, 2H), 7.30-7.35 (m, 1H), 7.13-7.19 (m, 1H), 6.94(d, J=8.16 Hz, 1H), 6.91 (d, J=7.78 Hz, 1H), 5.11 (s, 2H), 3.13-3.25 (m,1H), 2.65-2.88 (m, 3H), 2.56 (br d, J=9.41 Hz, 1H), 2.24 (s, 3H), 1.95(br s, 1H), 1.77-1.90 (m, 1H).

Example 73:6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16p:6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16p was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (200.00 mg, 480.91 μmol) and(5-methoxy-2-(trifluoromethyl)phenyl)boronic acid pinacol ester (242.14mg, 721.37 μmol) to provide Intermediate 16p (72.00 mg, crude) as yellowsolid. m/z (M+H)⁺=401.1.

Example 73:6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 73 was prepared following thesame procedure described for Example 58, starting from intermediate 16p(72.00 mg, 179.84 μmol), to provide Example 73 (8.30 mg, 19.84 μmol,11.03% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.8Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H),6.78 (d, J=2.5 Hz, 1H), 6.72 (dd, J=2.6, 8.3 Hz, 1H), 3.81 (s, 3H),3.19-2.99 (m, 2H), 2.88-2.78 (m, 1H), 2.75-2.61 (m, 2H), 2.32 (s, 3H),2.21-2.10 (m, 1H), 1.94-1.81 (m, 1H)

Example 74:6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16q:6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16q was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (200.00 mg, 480.91 μmol) and(2-fluoro-5-methoxyphenyl)boronic acid pinacol ester (122.60 mg, 721.37μmol) to provide Intermediate 16q (60.00 mg, crude) as brown solid. m/z(M+H)⁺=351.0.

Example 74:6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 74 was prepared following thesame procedure described for Example 58, starting from intermediate 16q(60.00 mg, 171.26 μmol), to provide Example 74 (7.70 mg, 21.66 μmol,12.65% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.9Hz, 2H), 7.70 (s, 1H), 7.43 (t, J=4.8 Hz, 1H), 7.10 (d, J=7.7 Hz, 1H),7.04-6.97 (m, 2H), 3.20-3.10 (m, 1H), 3.04 (br dd, J=5.1, 19.4 Hz, 1H),2.86-2.61 (m, 3H), 2.34 (s, 6H), 2.18-2.09 (m, 1H), 1.95-1.83 (m, 1H).

Example 75:6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16r:6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16r was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (200.00 mg, 480.91 μmol) and(2-chloro-5-methoxyphenyl)boronic acid pinacol ester (193.72 mg, 721.37μmol), to provide Intermediate 16r (160.00 mg, crude) as brown solid.m/z (M+H)⁺=367.0, 369.0.

Example 75:6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 75 was prepared following thesame procedure described for Example 58, starting from intermediate 16r(160.00 mg, 436.21 μmol), to provide Example 75 (5.80 mg, 15.65 μmol,3.59% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.9Hz, 2H), 7.71 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H),6.82 (d, J=2.9 Hz, 1H), 6.76 (dd, J=2.9, 8.7 Hz, 1H), 3.82 (s, 3H),3.48-3.37 (m, 1H), 3.08-2.93 (m, 2H), 2.76-2.57 (m, 2H), 2.25-2.16 (m,1H), 1.97-1.84 (m, 1H).

Example 76:6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16s:6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16s was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (200.00 mg, 480.91 μmol) and(5-methoxy-2-methylphenyl)boronic acid (119.73 mg, 721.37 μmol), toprovide Intermediate 16s (120.00 mg, crude) as yellow solid. m/z(M+H)⁺=347.1.

Example 76:6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 76 was prepared following thesame procedure described for Example 58, starting from intermediate 16s(120.00 mg, 346.44 μmol), to provide Example 76 (15.00 mg, 54.38 μmol,15.70% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.8Hz, 2H), 7.69 (s, 1H), 7.41 (t, J=4.9 Hz, 1H), 7.07-6.98 (m, 2H), 6.81(d, J=8.3 Hz, 1H), 3.83 (s, 3H), 3.39-3.26 (m, 1H), 3.06-2.85 (m, 2H),2.73-2.59 (m, 2H), 2.31 (s, 3H), 2.14 (br dd, J=3.5, 13.3 Hz, 1H),1.99-1.87 (m, 1H).

Example 77:6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16t:6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16t was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15b (250.00 mg, 500.95 μmol) and(2-methyl-5-(pyrrolidin-1-yl)phenyl)boronic acid pinacol ester (334.07mg, 751.43 μmol) to give intermediate 16t (110.00 mg, crude) as yellowsolid. m/z (M+H)⁺=386.2.

Example 77:6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 77 was prepared following thesame procedure described for Example 58, starting from intermediate 16t(110.00 mg, 285.37 μmol), to provide Example 77 (9.84 mg, 24.20 μmol,8.48% yield) as a yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.8Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.09-7.03 (m, 1H),6.46-6.40 (m, 2H), 3.31-3.25 (m, 4H), 3.18-3.01 (m, 2H), 2.87-2.62 (m,3H), 2.28 (s, 3H), 2.21-2.14 (m, 1H), 2.01 (td, J=3.3, 6.6 Hz, 4H),1.95-1.84 (m, 1H).

Example 78:6-(1-methylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16u:6-(1-methylindolin-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16u was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15b (250.00 mg, 500.94 μmol) and(1-methylindolin-4-yl)boronic acid pinacol ester (241.60 mg, 751.41μmol) to give intermediate 16u (140.00 mg, crude) as a yellow solid. m/z(M+H)⁺=358.2.

Example 78:6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 78 was prepared following thesame procedure described for Example 58, starting from intermediate 16u(140.00 mg, 391.71 μmol), to provide Example 78 (26.79 mg, 71.41 μmol,18.23% yield) as yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.9Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.9 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H),6.92 (dd, J=2.5, 8.3 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 3.79-3.66 (m, 1H),3.19-3.09 (m, 1H), 3.08-2.98 (m, 1H), 2.87-2.78 (m, 1H), 2.74-2.61 (m,2H), 2.32 (s, 3H), 2.19-2.10 (m, 1H), 1.93-1.79 (m, 1H), 0.79-0.76 (m,4H).

Example 79:6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16v:6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16v was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15b (250.00 mg, 500.95 μmol) and(2-fluoro-3-methoxyphenyl)boronic acid pinacol ester (189.43 mg, 751.42μmol) to give intermediate 16v (140.00 mg, crude) as a yellow solid. m/z(M+H)⁺=351.0.

Example 79:6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 79 was prepared following thesame procedure described for Example 58, starting from intermediate 16v(140.00 mg, 399.60 μmol), to provide Example 79 (9.04 mg, 25.45 μmol,6.37% yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.9Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.31-7.27 (m, 1H), 7.00(dd, J=1.7, 8.2 Hz, 1H), 6.93 (t, J=1.9 Hz, 1H), 6.88 (d, J=7.7 Hz, 1H),3.79-3.70 (m, 1H), 3.05-2.85 (m, 3H), 2.80-2.60 (m, 2H), 2.29-2.17 (m,1H), 1.95-1.81 (m, 1H), 0.83-0.77 (m, 4H).

Example 80:6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16w:6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16w was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (250.00 mg, 500.94 μmol) and(5-methoxy-2-methylphenyl)boronic acid (124.72 mg, 751.41 μmol), to giveintermediate 16w (110.00 mg, crude) as brown solid. m/z (M+H)⁺=347.1

Example 80:6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 80 was prepared following thesame procedure described for Example 58, starting from intermediate 16w(110.00 mg, 317.57 μmol), to provide Example 80 (23.99 mg, 68.58 μmol,21.60% yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H),9.02 (s, 1H), 7.85 (s, 1H), 7.71 (t, J=4.89 Hz, 1H), 7.16 (t, J=7.91 Hz,1H), 6.90 (d, J=7.53 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 6.08 (tdd,J=4.99, 10.42, 17.25 Hz, 1H), 5.43 (dd, J=1.76, 17.32 Hz, 1H), 5.26 (dd,J=1.69, 10.60 Hz, 1H), 4.56 (d, J=4.89 Hz, 2H), 3.12-3.24 (m, 1H),2.65-2.87 (m, 3H), 2.56 (br d, J=8.53 Hz, 1H), 2.22 (s, 3H), 1.95 (br s,1H), 1.79-1.91 (m, 1H).

Example 81:6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16x:6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16x was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (250.00 mg, 500.94 μmol) and(2,5-dimethylphenyl)boronic acid (112.70 mg, 751.41 μmol), to giveintermediate 16x (75.00 mg, crude) as yellow solid. m/z (M+H)⁺=331.2.

Example 81:6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 81 was prepared following thesame procedure described for Example 58, starting from intermediate 16x(75.00 mg, 227.01 μmol), to provide example 81 (16.9 mg, 50.69 μmol,22.33% yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.18 (s, 2H),7.78 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.91 Hz, 1H), 6.85 (d,J=8.03 Hz, 1H), 3.78 (s, 3H), 3.27-3.34 (m, 4H), 3.13-3.22 (m, 1H),2.65-2.83 (m, 3H), 2.52-2.58 (m, 1H), 2.18 (s, 3H), 1.91-2.05 (m, 5H),1.77-1.89 (m, 1H).

Example 82:6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16y:6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16y was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (250.00 mg, 500.94 μmol) and(2,3-dimethylphenyl)boronic acid (112.70 mg, 751.41 μmol), to provideintermediate 16y (100.00 mg, crude) as yellow solid. m/z (M+H)⁺=331.2.

Example 82:6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 82 was prepared following thesame procedure described for Example 58, starting from intermediate 16y(100.00 mg, 302.68 μmol), to provide Example 82 (4.78 mg, 13.70 μmol,4.53% yield) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.61 (s,2H), 7.81 (s, 1H), 7.14-7.22 (m, 1H), 6.88 (dd, J=7.91, 16.81 Hz, 2H),3.75-3.82 (m, 7H), 3.34 (br s, 4H), 3.12-3.22 (m, 1H), 2.76-2.86 (m,1H), 2.63-2.75 (m, 2H), 2.56 (br s, 1H), 2.18 (s, 3H), 1.94 (br s, 1H),1.77-1.90 (m, 1H).

Example 83:6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16z:6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16z was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (590 mg, 1.18 mmol) and(3-(methoxymethyl)phenyl)boronic acid (196.23 mg, 1.18 mmol), to provideintermediate 16z (280 mg, crude) as a yellow solid. m/z (M+H)⁺=347.1.

Example 83:6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 83 was prepared following thesame procedure described for Example 58, starting from intermediate 16z(260 mg, 750.62 μmol), to provide Example 83 (24.91 mg, 70.28 μmol,9.36% yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 2H),7.82 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.65 Hz, 1H), 6.85 (d,J=8.16 Hz, 1H), 5.03 (t, J=5.46 Hz, 1H), 4.24-4.31 (m, 2H), 3.75-3.80(m, 5H), 3.13-3.22 (m, 1H), 2.67-2.86 (m, 3H), 2.55 (br d, J=9.79 Hz,1H), 2.18 (s, 3H), 1.93 (br s, 1H), 1.78-1.89 (m, 1H).

Example 84:6-(5-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16aa:6-(5-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16aa was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (200 mg, 523.65 μmol) and(5-cyclopropoxy-2-methylphenyl)boronic acid pinacol ester (244.71 mg,785.47 μmol), to provide intermediate 16aa (210 mg, crude) as a yellowsolid. m/z (M+H)⁺=373.2.

Example 84:6-(5-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 84 was prepared following thesame procedure described for Example 58, starting from intermediate 16aa(210 mg, 563.88 μmol), to provide example 84 (13.78 mg, 36.77 μmol,6.52% yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.35 (d,J=6.15 Hz, 1H), 7.77 (s, 1H), 7.15-7.21 (m, 1H), 6.96 (d, J=6.27 Hz,1H), 6.89 (d, J=7.78 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 3.79 (s, 3H),3.67 (br d, J=5.02 Hz, 4H), 3.62 (br d, J=4.77 Hz, 4H), 3.17 (br t,J=8.97 Hz, 1H), 2.62-2.83 (m, 3H), 2.52-2.59 (m, 1H), 2.18 (s, 3H), 1.93(br s, 1H), 1.83 (dq, J=4.83, 11.90 Hz, 1H).

Example 85:6-(3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16ab:6-(3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16ab was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (200 mg, 523.65 μmol) and (3-cyclopropoxyphenyl)boronicacid pinacol ester (241.24 mg, 785.48 μmol), to provide intermediate16ab (170 mg, crude) as a yellow solid. m/z (M+H)⁺=359.2.

Example 85:6-(3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 85 was prepared following thesame procedure described for Example 58, starting from intermediate 16ab(170 mg, 474.34 μmol), to provide example 85 (12.36 mg, 33.03 μmol,6.96% yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.93 (d, J=4.8Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.9 Hz, 1H), 7.27-7.22 (m, 1H), 6.82(d, J=7.8 Hz, 1H), 6.80-6.76 (m, 2H), 4.78 (qd, J=2.9, 5.7 Hz, 1H),3.03-2.84 (m, 3H), 2.80-2.71 (m, 1H), 2.71-2.60 (m, 1H), 2.26-2.16 (m,1H), 1.96-1.78 (m, 7H), 1.68-1.59 (m, 2H).

Example 86:6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16ac:6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16ac was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (300 mg, 785.48 μmol) and(3-(cyclopentyloxy)phenyl)boronic acid pinacol ester (425.50 mg, 1.18mmol), to provide intermediate 16ac (240 mg, crude) as a yellow solid.m/z (M+H)⁺=387.1.

Example 86:6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 86 was prepared following thesame procedure described for Example 58, starting from intermediate 16ac(240 mg, 621.04 μmol), to provide Example 86 (29.15 mg, 73.01 μmol,11.76% yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.93 (d, J=4.8Hz, 2H), 7.70 (s, 1H), 7.42 (t, J=4.9 Hz, 1H), 7.27-7.22 (m, 1H), 6.82(d, J=7.8 Hz, 1H), 6.80-6.76 (m, 2H), 4.78 (qd, J=2.9, 5.7 Hz, 1H),3.03-2.84 (m, 3H), 2.80-2.71 (m, 1H), 2.71-2.60 (m, 1H), 2.26-2.16 (m,1H), 1.96-1.78 (m, 7H), 1.68-1.59 (m, 2H).

Example 87:6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16ad:6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16ad was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (0.3 g, 801.51 μmol) and(4-methoxy-2-methylphenyl)boronic acid (133.04 mg, 801.51 μmol), toprovide Intermediate 16ad (0.2 g, crude) as yellow solid. m/z(M+H)⁺=347.1; ¹H NMR (DMSO-d₆, 400 MHz) δ 9.02 (d, J=4.8 Hz, 2H), 8.00(s, 1H), 7.71 (t, J=4.8 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.86 (d, J=2.4Hz, 1H), 6.81 (dd, J=8.4, 2.4 Hz, 1H), 6.40 (s, 1H), 3.75 (s, 3H),2.75-2.85 (m, 2H), 2.60-2.70 (m, 2H), 2.36 (s, 3H).

Example 87:6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 87 was prepared following thesame procedure described for Example 58, starting from intermediate 16ad(0.15 g, 433.05 μmol), to provide Example 87 (42 mg, 120.55 μmol, 27.84%yield) as white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=4.8 Hz,2H), 7.85 (s, 1H), 7.71 (t, J=4.8 Hz, 1H), 7.13-7.23 (m, 1H), 6.77 (brd, J=2.8 Hz, 2H), 3.72 (s, 3H), 3.07 (m, 1H), 2.57-2.85 (m, 4H), 2.32(s, 3H), 1.78-1.99 (m, 2H).

Example 88:6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16ae:6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16ae was preparedfollowing the procedure described for Intermediate 16a, usingintermediate 15b (0.2 g, 534.34 μmol) and(1,5-dimethyl-1H-indazol-4-yl)boronic acid pinacol ester (145.42 mg,534.34 μmol) to provide intermediate 16ae (50 mg, 134.99 μmol, 25.26%yield) as yellow solid. m/z (M+H)⁺=371.2.

Example 88:6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 88 was prepared following thesame procedure described for Example 58, starting from intermediate 16ae(51.39 mg, 138.73 μmol), to provide example 88 (4 mg, 10.74 μmol, 7.74%yield) as light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.03 (d, J=4.8Hz, 3H), 8.24 (s, 1H), 7.85 (s, 1H), 7.68-7.76 (m, 1H), 7.41 (d, J=8.4Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.01 (s, 3H), 3.19 (m, 1H), 3.12-3.12(m, 1H), 2.73-2.94 (m, 4H), 2.44 (s, 3H), 1.99 (m, 2H).

Example 89:6-mesityl-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, wasPrepared According to Scheme 2, Method A

Intermediate 16af:6-mesityl-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16af was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (200.00 mg, 534.34 μmol) and mesitylboronic acid (87.64mg, 534.34 μmol) to provide intermediate 16af (0.15 g, 435.53 μmol,81.51% yield) as yellow solid. m/z (M+H)⁺=345.3; ¹H NMR (DMSO-d₆, 400MHz) δ 9.03 (d, J=4.8 Hz, 2H), 7.99 (s, 1H), 7.71 (t, J=4.8 Hz, 1H),6.92 (s, 2H), 6.26 (s, 1H), 2.78-2.91 (m, 2H), 2.52-2.56 (m, 2H), 2.24(s, 3H), 2.20 (s, 6H).

Example 89:6-mesityl-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 89 was prepared following thesame procedure described for Example 58, starting from intermediate 16af(150.00 mg, 435.53 μmol), to provide Example 89 (8 mg, 22.61 μmol, 5.19%yield) as white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.01 (d, J=4.8 Hz,2H), 7.81 (s, 1H), 7.67-7.73 (m, 1H), 6.81 (s, 2H), 3.28-3.30 (m, 1H),2.95-3.08 (m, 1H), 2.64-2.84 (m, 2H), 2.32 (s, 6H), 2.18 (s, 3H), 1.89(m, 2H).

Example 90:6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16ag:6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16ag was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (0.2 g, 534.34 μmol) and(2,6-difluoro-3-methoxyphenyl)boronic acid (100.42 mg, 534.34 μmol) toprovide intermediate 16ag (0.15 g, 407.24 μmol, 76.21% yield) as yellowsolid. m/z (M+H)⁺=369.1; ¹H NMR (DMSO-d₆, 400 MHz) δ 9.03 (d, J=4.8 Hz,2H), 8.04 (s, 1H), 7.72 (t, J=4.8 Hz, 1H), 7.06-7.34 (m, 2H), 6.71 (s,1H), 3.86 (s, 3H), 2.76-2.89 (m, 2H), 2.62-2.73 (m, 2H).

Example 90:6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 90 was prepared following thesame procedure described for Example 58, starting from intermediate 16ag(0.15 g, 407.24 μmol), to provide Example 90 (60 mg, 162.01 μmol, 39.78%yield) as white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=4.8 Hz,2H), 7.83 (s, 1H), 7.71 (t, J=4.8 Hz, 1H), 6.99-7.19 (m, 3H), 3.83 (s,3H), 3.36-3.43 (m, 1H), 2.71-3.04 (m, 4H), 1.97-2.18 (m, 3H).

Example 91:6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16ah:6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16ah was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (2.50 g, 6.68 mmol) and(2-chloro-3-cyclopropoxyphenyl)boronic acid pinacol ester (1.83 g, 6.21mmol) to provide intermediate 16ah (1.60 g, 3.84 mmol, 57.4% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.8 Hz, 2H), 7.79 (s,1H), 7.42 (t, J=4.8 Hz, 1H), 7.35-7.30 (m, 1H), 7.29-7.24 (m, 2H), 6.91(dd, J=1.6, 7.6 Hz, 1H), 6.35 (t, J=1.6 Hz, 1H), 3.84 (tt, J=3.2, 5.9Hz, 1H), 3.08-2.98 (m, 2H), 2.84-2.72 (m, 2H), 0.92-0.82 (m, 4H).

Example 91:6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

According to scheme 2, step ix: Example 91 was prepared following thesame procedure described for Example 58 starting from intermediate 16ah(1.20 g, 2.88 mmol), to provide Example 91 (517 mg, 1.26 mmol, 43.9%yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.93 (d, J=4.8 Hz,2H), 7.70 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.26-7.22 (m, 2H), 6.95-6.86(m, 1H), 3.83 (tt, J=3.0, 5.8 Hz, 1H), 3.58-3.47 (m, 1H), 3.04-2.92 (m,2H), 2.82-2.57 (m, 2H), 2.24-2.14 (m, 1H), 1.99-1.86 (m, 1H), 0.93-0.80(m, 4H).

Example 92:6-(1-cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16ai:6-(1-cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16ai was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15b (2.00 g, 5.34 mmol) and1-cyclopropylindolin-4-yl)boronic acid pinacol ester (1.50 g, 5.26mmol), to provide Intermediate 16ai (1.70 g, 4.43 mmol, 83.0% yield) ayellow solid. m/z (M+H)⁺=384.0

Example 92:6-(1-cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 92 was prepared following asimilar procedure than for Example 58, starting from intermediate 16ai(1.70 g, 4.43 mmol to provide Example 92 (230 mg, 549.19 μmol, 35.10%yield) as a light-yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.8Hz, 1H), 8.97-8.90 (m, 1H), 7.69 (s, 1H), 7.42 (t, J=5.0 Hz, 1H), 7.13(t, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.61 (d, J=7.6 Hz, 1H),3.46-3.39 (m, 2H), 3.06-2.89 (m, 4H), 2.85-2.59 (m, 3H), 2.19-2.11 (m,2H), 1.95-1.83 (m, 1H), 0.73-0.63 (m, 4H).

Example 93:6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16aj:6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16aj was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15c (3.00 g, 7.49 mmol) and(3-cyclopropoxy-2-methylphenyl)boronic acid pinacol ester (2.25 g, 7.49mmol), to provide Intermediate 16aj (2.10 g, 5.28 mmol, 70.5% yield) asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 2H), 7.75 (s, 1H),7.25-7.16 (m, 2H), 6.81 (dd, J=1.8, 7.0 Hz, 1H), 6.23 (s, 1H), 3.80-3.73(m, 1H), 3.03-2.94 (m, 2H), 2.72-2.63 (m, 2H), 2.43 (s, 3H), 2.18 (s,3H), 0.85-0.73 (m, 4H).

Example 93:6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 93 was prepared following thesame procedure described for Example 58, starting from intermediate 16aj(1.20 g, 3.02 mmol), to provide Example 93 (500 mg, 1.27 mmol, 42.1%yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.74 (s, 2H), 7.68(s, 1H), 7.24-7.13 (m, 2H), 6.86 (d, J=6.5 Hz, 1H), 3.78-3.71 (m, 1H),3.26-3.17 (m, 1H), 3.04-2.95 (m, 1H), 2.86-2.76 (m, 1H), 2.75-2.60 (m,2H), 2.43 (s, 3H), 2.19 (s, 3H), 2.17-2.09 (m, 1H), 1.95-1.82 (m, 1H),0.82-0.76 (m, 4H).

Example 94:6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method A

Intermediate 16ak:6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16ak was preparedfollowing the procedure described for Intermediate 16a, starting fromintermediate 15c (3.00 g, 7.49 mmol) and(2-chloro-3-methoxyphenyl)boronic acid pinacol ester (1.40 g, 7.49mmol), to provide Intermediate 16ak (2.40 g, 6.15 mmol, 82.1% yield,97.6% purity) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 2H),7.83-7.74 (m, 1H), 7.33-7.21 (m, 1H), 7.04-6.81 (m, 2H), 6.36 (s, 1H),4.10-3.89 (m, 3H), 3.18-2.96 (m, 2H), 2.88-2.73 (m, 2H), 2.44 (s, 3H).

Example 94:6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 94 was prepared following thesame procedure described for Example 58, starting from intermediate 16ak(600 mg, 1.54 mmol), to provide Example 94 (230 mg, 588 μmol, 38.2%yield, 97.8% purity) was obtained as a white solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.73 (s, 2H), 7.69 (s, 1H), 7.26-7.23 (m, 1H), 6.88 (dd, J=4.4,8.0 Hz, 2H), 3.93 (s, 3H), 3.61-3.49 (m, 1H), 3.02-2.92 (m, 2H),2.82-2.58 (m, 2H), 2.43 (s, 3H), 2.19 (td, J=2.8, 10.0 Hz, 1H),1.98-1.85 (m, 1H).

Example 95:6-(2-chloro-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method B

Intermediate 17a:2-(pyrimidin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to Scheme 2, step x: To a solution of intermediate 15b (1 g,2.67 mmol, 1 eq), Pd(dppf)Cl₂ (97.74 mg, 133.58 μmol, 0.05 eq) and KOAc(524.41 mg, 5.34 mmol, 2 eq) in dioxane (20 mL) was added Pin₂B₂ (1.02g, 4.01 mmol, 1.5 eq) in one portion at 25° C. under N₂. The mixture wasstirred at 100° C. for 12 hours. The mixture was filtered, the filtratewas concentrated under reduced pressure to give a residue. The residuewas purified by silica gel chromatography (PE:EtOAc=1:1) to affordintermediate 17a (0.85 g, 2.41 mmol, 90.33% yield) as a yellow solid.

m/z (M+H)⁺=353.3; ¹H NMR (CDCl₃, 400 MHz) δ 8.92 (d, J=4.8 Hz, 2H), 7.77(s, 1H), 7.41 (t, J=4.8 Hz, 1H), 6.99 (s, 1H), 2.74-2.89 (t, J=8.8 Hz,2H), 2.46-2.61 (t, J=8.8 Hz, 2H), 1.32 (s, 12H).

Intermediate 16a1:6-(2-chloro-4-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to Scheme 2, step xi: To a mixture of intermediate 17a (247.04mg, 1.20 mmol, 64.34 μL, 1.5 eq) and 1-bromo-2-chloro-4-methylbenzene(0.3 g, 801.51 μmol, 1 eq) in dioxane (10 mL) was added Na₂CO₃ (339.80mg, 3.21 mmol, 4 eq) in H₂O (1 mL) and Pd(dppf)Cl₂.CH₂Cl₂ (65.45 mg,80.15 μmol, 0.1 eq) in one portion at 20° C. under N₂. The mixture wasstirred at 100° C. for 12 hours. The mixture was filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (PE:EtOAc=0:1, 1:0) to afford intermediate 16a1 (0.15 g,427.59 μmol, 53.35% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ9.07-9.03 (m, 3H), 8.04 (s, 1H), 7.76-7.68 (m, 2H), 7.40 (s, 1H), 7.34(d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.57 (s, 1H), 2.87-2.79 (m,2H), 2.77-2.67 (m, 2H), 2.35 (s, 3H).

Example 95:6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 95 was prepared following thesame procedure described for Example 58, starting from intermediate 16a1(0.15 g, 427.59 μmol) to yield Example 95 (0.018 g, 51.02 μmol, 11.93%yield) as a white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.0 Hz,2H), 7.71 (s, 1H), 7.42 (t, J=4.4 Hz, 1H), 7.25 (s, 1H), 7.17-7.12 (m,1H), 7.12-7.06 (m, 1H), 3.52-3.39 (m, 1H), 3.04-2.92 (m, 2H), 2.76-2.58(m, 2H), 2.34 (s, 3H), 2.22-2.05 (m, 2H), 1.97-1.85 (m, 1H).

Example 96:6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method B

Intermediate 16 am:6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to Scheme 2, step xi: intermediate 16 am was preparedfollowing the same procedure described for intermediate 16a1, startingfrom intermediate 17a (0.2 g, 567.87 μmol) and3-bromo-N,N,2-trimethylaniline (121.58 mg, 567.87 μmol) to yieldintermediate 16 am (0.15 g, 417.33 μmol, 73.49% yield) as yellow solid.m/z (M+H)⁺=360.3; ¹H NMR (CDCl₃, 400 MHz) δ 8.94 (d, J=4.9 Hz, 3H), 7.78(s, 1H), 7.44-7.40 (m, 2H), 7.20 (t, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz,1H), 6.90 (d, J=7.6 Hz, 1H), 6.26 (s, 1H), 2.96-3.07 (m, 2H), 2.66-2.76(m, 8H), 2.35 (s, 3H).

Example 96:6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 96 was prepared following thesame procedure described for Example 58, starting from intermediate 16am (0.15 g, 417.33 μmol) to yield Example 96 (14 mg, 34.93 μmol, 8.37%yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.8 Hz, 2H),7.70 (s, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.28 (m, 1H), 7.02 (d, J=8.0 Hz,1H), 6.98 (d, J=8.0 Hz, 1H), 3.16 (m, 1H), 2.97-2.92 (m, 1H), 2.91-2.75(m, 7H), 2.65-2.59 (m, 2H), 2.35 (s, 3H), 2.08-2.06 (m, 1H), 1.86-1.81(m, 1H).

Example 97:6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method B

Intermediate 16an:6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to Scheme 2, step xi: intermediate 16an was prepared followingthe same procedure described for intermediate 16a1, starting fromintermediate 17a (0.3 g, 851.80 μmol) and1-bromo-5-methoxy-2,4-dimethylbenzene (183.21 mg, 851.80 μmol) to yieldintermediate 16an (0.2 g, 554.93 μmol, 65.15% yield) as yellow solid.m/z (M+H)⁺=361.3; ¹H NMR (CDCl₃, 400 MHz) δ 9.03 (d, J=4.8 Hz, 2H), 8.01(s, 1H), 7.71 (t, J=4.8 Hz, 1H), 7.04 (s, 1H), 6.80 (s, 1H), 6.44 (s,1H), 3.79 (s, 3H), 2.76-2.89 (m, 2H), 2.61-2.73 (m, 2H), 2.26 (s, 3H),2.14 (s, 3H).

Example 97:6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 97 was prepared following thesame procedure described for Example 58, starting from intermediate 16nj(0.2 g, 554.93 μmol) to yield Example 97 (8 mg, 22.07 μmol, 3.98% yield)as white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=4.4 Hz, 2H), 7.86(s, 1H), 7.71 (t, J=4.4 Hz, 1H), 6.93 (s, 1H), 6.83 (s, 1H), 3.77 (s,3H), 3.07 (m, 1H), 2.72-2.88 (m, 4H), 2.23 (s, 3H), 2.09 (s, 3H),1.78-2.01 (m, 2H).

Example 986-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method B

Intermediate 16ao:6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 2, step viii: Intermediate 16ao was preparedfollowing the procedure described for intermediate 16a in Example 58,starting from intermediate 15b (0.3 g, 801.51 μmol) and(4-chloro-2-methylphenyl)boronic acid (136.58 mg, 801.51 μmol) to giveintermediate 16ao (0.15 g, 427.59 μmol, 53.35% yield) as yellow solid.m/z (M+H)⁺=351.1.

Example 98:6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 98 was prepared following thesame procedure described for Example 58, starting from intermediate 16ao(120 mg, 342.07 μmol) to yield Example 98 (13 mg, 36.85 μmol, 10.77%yield) as white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=4.8 Hz,2H), 7.85 (s, 1H), 7.71 (t, J=4.8 Hz, 1H), 7.22-7.34 (m, 3H), 3.14 (m,1H), 2.65-2.89 (m, 4H), 2.36 (s, 2H), 1.81-2.01 (m, 2H).

Example 99:6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 2, Method B

Intermediate 16ap:6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to Scheme 2, step xi: intermediate 16ap was prepared followingthe same procedure described for intermediate 16a1, starting fromintermediate 17a (0.3 g, 851.80 μmol) and1-(4-bromo-3-methylphenyl)ethan-1-one (181.49 mg, 851.80 μmol) toprovide intermediate 16ap (0.18 g, 502.24 μmol, 58.96% yield) as yellowsolid. m/z (M+H)⁺=359.2; ¹H NMR (DMSO-d₆, 400 MHz) δ 9.03 (d, J=4.8 Hz,2H), 8.03 (s, 1H), 7.88 (s, 1H), 7.83 (br d, J=8.0 Hz, 1H), 7.72 (t,J=4.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.52 (s, 1H), 2.80-2.89 (m, 2H),2.66-2.75 (m, 2H), 2.59 (s, 3H), 2.44 (s, 3H).

Example 99:6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step ix: Example 99 was prepared following thesame procedure described for Example 58, starting from intermediate 16ap(150.00 mg, 418.53 μmol) to yield Example 99 (22 mg, 61.04 μmol, 14.58%yield) as white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=4.8 Hz,2H), 7.85 (s, 1H), 7.76-7.83 (m, 2H), 7.71 (t, J=4.8 Hz, 1H), 7.43 (brd, J=8.0 Hz, 1H), 3.16-3.27 (m, 1H), 2.65-2.93 (m, 4H), 2.55 (s, 3H),2.43 (s, 3H), 1.83-2.03 (m, 2H).

Example 100:6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 5

Intermediate 50:6-(3-hydroxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

According to Scheme 5, step i: To a solution of compound Example 40(2.50 g, 7.18 mmol, 1.00 eq) in CH₂Cl₂ (30.00 mL) was added BBr₃ (8.99g, 35.90 mmol, 3.46 mL, 5.00 eq) dropwise at 0° C. under N₂. The mixturewas stirred at 0° C. for 1.5 hours. The mixture was poured into H₂O (80mL) at 0° C. The pH of aqueous phase was adjusted about 6-7 by additionof K₂CO₃ solid. Large quantities precipitate formed. The mixture wasfiltered and the combined aqueous phase was extracted with CH₂Cl₂ (60mL×5), filtered and concentrated in vacuo. The filter cake was dissolvedwith CH₂Cl₂/MeOH (1/10, 100 mL) and stirred for 1 hour. The mixture wasfiltered. All organic phases were combined and dried in vacuo.Intermediate 50 was obtained (2.60 g, 5.99 mmol, 83.39% yield) as abrown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 9.01 (s, 1H),7.85 (s, 1H), 7.71 (t, J=4.89 Hz, 1H), 6.88-6.95 (m, 1H), 6.63-6.69 (m,1H), 6.60 (d, J=7.65 Hz, 1H), 3.07-3.15 (m, 1H), 2.66-2.85 (m, 3H), 2.56(br s, 1H), 2.13 (s, 3H), 1.91-1.99 (m, 1H), 1.74-1.86 (m, 1H).

Example 100:(6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one

According to Scheme 5, step ii A mixture of intermediate 50 (80 mg,239.26 μmol, 1 eq) and 1-bromo-3-methoxypropane (73.22 mg, 478.52 μmol,38.27 μL, 2 eq) in DMF (2 mL) was added Cs₂CO₃ (116.93 mg, 358.89 μmol,1.5 eq) in one portion at 25° C. under N₂. The mixture was stirred at100° C. for 12 hours. The mixture was filtered and the filtrate wasconcentrated under reduced pressure and purified by prep-HPLC to affordExample 100 (25 mg, 61.50 μmol, 25.71% yield) as a white solid. ¹H-NMR(400 MHz, DMSO-d₆) δ 9.02 (d, J=4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (t,J=4.8 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.80-6.93 (m, 2H), 4.00 (t, J=6.2Hz, 2H), 3.51 (t, J=6.2 Hz, 2H), 3.26 (s, 3H), 3.16-3.19 (m, 1H),2.58-2.87 (m, 4H), 2.19 (s, 3H), 1.76-2.02 (m, 4H).

Example 101:6-(3-ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 5

According to Scheme 5, step ii: Example 101 was prepared following thesame procedure described for Example 100, starting from intermediate 50(80 mg, 239.26 μmol) and iodoethane (74.63 mg, 478.51 μmol) to yieldintermediate Example 101 (25 mg, 68.98 μmol, 28.83% yield) as whitesolid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.02 (d, J=4.8 Hz, 2H), 7.84 (s, 1H),7.71 (br t, J=4.8 Hz, 1H), 7.15 (br t, J=7.8 Hz, 1H), 7.07-7.26 (m, 1H),6.85 (br dd, J=19.0, 7.8 Hz, 2H), 4.01 (q, J=6.8 Hz, 2H), 3.16-3.18 (m,1H), 2.56-2.93 (m, 4H), 2.19 (s, 3H), 1.75-2.03 (m, 2H), 1.36 (br t,J=6.8 Hz, 3H).

Example 102:6-(3-(cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 5

According to Scheme 5, step ii: Example 102 was prepared following thesame procedure described for Example 100, starting from intermediate 50(150.00 mg, 345.43 μmol) and (bromomethyl)cyclopropane (233.16 mg, 1.73mmol) to yield intermediate Example 102 ((58.63 mg, 150.78 μmol, 43.65%yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 9.02(s, 1H), 7.85 (s, 1H), 7.71 (t, J=4.83 Hz, 1H), 7.10-7.17 (m, 1H), 6.88(d, J=7.65 Hz, 1H), 6.81 (d, J=8.16 Hz, 1H), 3.82 (d, J=6.65 Hz, 2H),3.12-3.23 (m, 1H), 2.65-2.87 (m, 3H), 2.52-2.62 (m, 1H), 2.21 (s, 3H),1.94 (br s, 1H), 1.76-1.89 (m, 1H), 1.19-1.30 (m, 1H), 0.52-0.61 (m,2H), 0.29-0.37 (m, 2H).

Example 103:6-(3-isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 5

According to Scheme 5, step ii: Example 103 was prepared following thesame procedure described for Example 100, starting from intermediate 50(180.00 mg, 414.51 μmol) and 2-bromopropane (352.31 mg, 2.07 mmol) toyield intermediate Example 103 (71.78 mg, 190.68 μmol, 46.00% yield) asa white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 9.02 (s, 1H),7.85 (s, 1H), 7.72 (t, J=4.89 Hz, 1H), 7.12-7.18 (m, 1H), 6.88 (d,J=3.39 Hz, 1H), 6.86 (d, J=3.89 Hz, 1H), 4.43-4.71 (m, 1H), 3.12-3.22(m, 1H), 2.66-2.86 (m, 3H), 2.56 (br d, J=9.91 Hz, 1H), 2.18 (s, 3H),1.91-2.00 (m, 1H), 1.79-1.90 (m, 1H), 1.28 (d, J=6.02 Hz, 6H).

Example 104:6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was prepared according to Scheme 5

According to Scheme 5, step ii: Example 104 was prepared following thesame procedure described for Example 100, starting from intermediate 50(150 mg, 345.42 μmol) and 2-bromocyclopropane (417.88 mg, 3.45 mmol) toyield intermediate Example 104 (19.84 mg, 51.56 μmol, 14.93% yield) as awhite solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 9.02 (s, 1H),7.85 (s, 1H), 7.71 (t, J=4.89 Hz, 1H), 7.16 (t, J=7.91 Hz, 1H), 6.90 (d,J=7.53 Hz, 1H), 6.85 (d, J=8.16 Hz, 1H), 6.08 (tdd, J=4.99, 10.42, 17.25Hz, 1H), 5.43 (dd, J=1.76, 17.32 Hz, 1H), 5.26 (dd, J=1.69, 10.60 Hz,1H), 4.56 (d, J=4.89 Hz, 2H), 3.12-3.24 (m, 1H), 2.65-2.87 (m, 3H), 2.56(br d, J=8.53 Hz, 1H), 2.22 (s, 3H), 1.95 (br s, 1H), 1.79-1.91 (m, 1H).

Example 105:6-(3-(2-methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was prepared according to Scheme 5

According to Scheme 5, step ii: Example 105 was prepared following thesame procedure described for Example 100, starting from intermediate 50(200.00 mg, 460.57 μmol) and 1-bromo-2-methoxyethane (320.07 mg, 2.30mmol) to yield intermediate Example 105 (41.81 mg, 106.54 μmol, 23.13%yield) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 9.02(s, 1H), 7.86 (s, 1H), 7.72 (t, J=4.89 Hz, 1H), 7.12-7.20 (m, 1H), 6.90(d, J=7.65 Hz, 1H), 6.86 (d, J=8.03 Hz, 1H), 4.09 (dd, J=3.89, 5.40 Hz,2H), 3.66-3.74 (m, 2H), 3.12-3.23 (m, 1H), 2.65-2.88 (m, 3H), 2.57 (brd, J=8.28 Hz, 1H), 2.20 (s, 3H), 1.95 (br s, 1H), 1.78-1.90 (m, 1H).

Example 106:6-(3-(benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 5

According to Scheme 5, step ii: Example 106 was prepared following thesame procedure described for Example 100, starting from intermediate 50(180.00 mg, 414.51 μmol) and (bromomethyl)benzene (212.68 mg, 1.24 mmol)to yield intermediate Example 106 (61.03 mg, 143.77 μmol, 34.68% yield)as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 9.01 (s,1H), 7.85 (s, 1H), 7.71 (t, J=4.83 Hz, 1H), 7.45-7.51 (m, 2H), 7.41 (t,J=7.40 Hz, 2H), 7.30-7.35 (m, 1H), 7.13-7.19 (m, 1H), 6.94 (d, J=8.16Hz, 1H), 6.91 (d, J=7.78 Hz, 1H), 5.11 (s, 2H), 3.13-3.25 (m, 1H),2.65-2.88 (m, 3H), 2.56 (br d, J=9.41 Hz, 1H), 2.24 (s, 3H), 1.95 (br s,1H), 1.77-1.90 (m, 1H).

Example 107:2-(5-cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method A

Intermediate 52a:2-(5-bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step i: To a mixture of Intermediate 7c (0.1 g,369.92 μmol, 1 eq) and 2,5-dibromopyrimidine (263.99 mg, 1.11 mmol, 3eq) in dioxane (20 mL) was added CuI (35.23 mg, 184.96 μmol, 0.5 eq),K₃PO₄ (196.31 mg, 924.81 μmol, 2.5 eq) and DMEDA (16.30 mg, 184.96 μmol,0.5 eq) in one portion at 25° C. under N₂. The mixture was stirred at25° C. for 5 min, then heated to 110° C. and stirred for 12 hours. Thereaction mixture was filtered and the filter was concentrated. Theresidue was purified by silica gel chromatography (PE:EtOAc=15/1˜1/1) toprovide intermediate 52a (0.08 g, 187.22 μmol, 50.61% yield) as a yellowsolid. ¹H NMR: (CDCl₃, 400 MHz) H) δ 8.88 (s, 2H), 7.61 (s, 1H), 7.05(d, J=8.4 Hz, 1H), 6.75-6.58 (m, 2H), 3.73 (s, 3H), 3.07-2.85 (m, 2H),2.75-2.65 (m, 1H), 2.61-2.57 (m, 2H), 2.23 (s, 3H), 2.08-2.05 (m, 1H),1.81-1.76 (m, 1H).

Example 1072-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step ii: To a mixture of intermediate 52a (0.2 g,468.06 μmol, 1 eq) and cyclopropylboronic acid (78.25 mg, 0.94 mmol, 5eq) in dioxane (20 mL) was added Pd(dppf)Cl₂ (17.12 mg, 23.40 μmol, 0.05eq) and K₂CO₃ (77.61 mg, 0.56 mmol, 3.0 eq) in one portion at 25° C.under N₂. The mixture was stirred at 25° C. for 5 min, then heated to110° C. and stirred for 12 hours. The reaction mixture was filtered andthe filter was concentrated. The residue was pre-purified by columnchromatography followed by preparative HPLC, to provide the Example 107(0.053 g, 136.44 μmol, 29.15% yield) as a white solid. ¹H-NMR (400 MHz,CDCl₃) δ 8.77 (s, 2H), 7.84 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.84 (d,J=2.4 Hz, 1H), 6.73 (dd, J=2.4, 8.4 Hz, 1H), 3.78 (s, 3H), 3.11 (m, 1H),2.80-2.52 (m, 4H), 2.28 (s, 3H), 2.09-2.06 (m, 1H), 1.93-1.84 (m, 3H),1.14-1.14 (m, 2H), 1.00-0.97 (m, 2H).

Example 108:2-(5-cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method A

Intermediate 52b:2-(5-bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step i: Intermediate 52b was prepared followingthe same procedure described for intermediate 52a, starting fromIntermediate 7a (0.5 g, 1.97 mmol) and 2,5-dibromopyridine (558.87 mg,2.36 mmol), to provide intermediate 52b (0.7 g, 1.71 mmol, 86.78% yield)was obtained as a light-yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s,1H), 7.98 (dd, J=8.4, 2.0 Hz, 1H), 7.80-7.66 (m, 2H), 7.18-6.95 (m, 3H),3.14 (m, 1H), 3.06-2.93 (m, 1H), 2.86-2.76 (m, 1H), 2.76-2.61 (m, 2H),2.35 (s, 3H), 2.32 (s, 3H), 2.14 (m, H), 1.96-1.78 (m, 1H).

Example 1082-(5-cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step ii: Example 108 was prepared following thesame procedure described for intermediate Example 107, starting fromIntermediate 52b (0.2, 487.44 μmol) and cyclopropylboronic acid (209.35mg, 2.44 mmol) to provide Example 108 (0.08 g, 213.20 μmol, 43.74%yield) as white solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.63 (s, 2H), 7.69 (s,1H), 7.17-6.97 (m, 3H), 3.14 (m, 1H), 3.00 (m, 1H), 2.86-2.76 (m, 1H),2.75-2.59 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12 (m, 1H), 2.03-1.95(m, 1H), 1.98 (m, 1H), 1.93-1.77 (m, 1H), 1.25-1.10 (m, 2H), 0.88 (m,2H).

Example 109:2-(5-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method A

Intermediate 52c:2-(5-bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step i: Intermediate 52c was prepared followingthe same procedure described for intermediate 52a, starting fromIntermediate 7a (1 g, 3.93 mmol) and 2,5-dibromopyrimidine (1.12 g, 4.72mmol), to provide intermediate 52c (1.2 g, 2.92 mmol, 74.20% yield) wasobtained as a light-yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s,2H), 7.69 (s, 1H), 7.14-6.99 (m, 3H), 3.26-3.09 (m, 1H), 3.00 (m, 1H),2.86-2.75 (m, 1H), 2.75-2.59 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.12(m, 1H), 1.93-1.79 (m, 1H).

Example 1092-(5-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step ii: Example 109 was prepared following thesame procedure described for intermediate Example 107, starting fromIntermediate 52c (200.48 mg, 487.44 μmol) and cyclopropylboronic acid(209.35 mg, 2.44 mmol) to provide Example 109 (0.124 g, 329.59 μmol,67.62% yield) as light-yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.44 (s,1H), 7.71 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.46 (dd, J=2.0, 8.4 Hz, 1H),7.13-7.07 (m, 1H), 7.06-7.00 (m, 2H), 3.19-3.09 (m, 1H), 3.04-2.92 (m,1H), 2.85-2.76 (m, 1H), 2.74-2.58 (m, 2H), 2.35 (s, 3H), 2.32 (s, 3H),2.15-2.10 (m, 1H), 2.03-1.94 (m, 1H), 1.93-1.81 (m, 1H), 1.13-1.05 (m,2H), 0.82-0.74 (m, 2H).

Example 110:2-(5-cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method A

Intermediate 52d:2-(5-bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step i: Intermediate 52d was prepared followingthe same procedure described for intermediate 52a, starting fromIntermediate 7b (1 g, 3.70 mmol) and 2,5-dibromopyridine (2.63 g, 11.10mmol), to provide intermediate 52d (1.2 g, 2.81 mmol, 76.09% yield) asyellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.76 (m, 1H), 8.28 (dd, J=2.0,8.4 Hz, 1H), 7.95 (m, 1H), 7.63 (br s, 1H), 7.18 (t, J=8.0 Hz, 1H),7.00-6.85 (m, 2H), 3.79 (s, 3H), 3.17 (m, 1H), 2.87-2.65 (m, 4H), 2.25(m, 1H), 2.18 (s, 3H), 1.88-1.81 (m, 1H).

Example 110:2-(5-cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step ii: Example 110 was prepared following thesame procedure described for intermediate Example 107, starting fromIntermediate 52d (0.3 g, 703.72 μmol) and cyclopropylboronic acid(302.24 mg, 3.52 mmol) to provide Example 110 (0.09 g, 232.27 μmol,33.01% yield) as yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 1H),7.83 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.19 (t,J=8.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 3.79 (s,3H), 3.15 (m, 1H), 2.87-2.65 (m, 4H), 2.34 (m, 1H), 2.18 (s, 3H), 2.05(m, 1H), 1.85 (m, 1H), 1.08-1.05 (m, 2H), 0.83 (m, 2H).

Example 111:6-(3-methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method B

According to scheme 6, step iii: To a mixture of Example 43 (180 mg,470.17 μmol, 1 eq) and pyrrolidine (66.88 mg, 940.33 μmol, 78.49 μL, 2eq) in dioxane (5 mL) were added RUPHOS precatalyst (36.52 mg, 47.02μmol, 0.1 eq) and Cs₂CO₃ (382.97 mg, 1.18 mmol, 2.5 eq) at 20° C. underN₂. The mixture was stirred at 100° C. for 12 hours. The mixture waspoured into H₂O (15 mL). The aqueous phase was filtered and extractedwith CH₂Cl₂ (20 mL×2). The combined organic phase was concentrated invacuo and combined with the filter cake to give the crude product whichwas purified by prep-HPLC. Example 111 (0.98 mg, 2.21 μmol, 0.5% yield)was obtained as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.18 (s, 2H),7.78 (s, 1H), 7.14-7.21 (m, 1H), 6.89 (d, J=7.91 Hz, 1H), 6.85 (d,J=8.03 Hz, 1H), 3.78 (s, 3H), 3.27-3.34 (m, 4H), 3.13-3.22 (m, 1H),2.65-2.83 (m, 3H), 2.52-2.58 (m, 1H), 2.18 (s, 3H), 1.91-2.05 (m, 5H),1.77-1.89 (m, 1H).

Example 112:(6-(3-methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method B

According to Scheme 6, step iii: Example 112 was prepared following thesame procedure described for Example 111, starting from Example 43 (150mg, 391.81 μmol) and morpholine (68.27 mg, 783.61 μmol, 68.96 μL) toprovide Example 112 (37.27 mg, 83.31 μmol, 21.26% yield) as a whitesolid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.61 (s, 2H), 7.81 (s, 1H), 7.14-7.22(m, 1H), 6.88 (dd, J=7.91, 16.81 Hz, 2H), 3.75-3.82 (m, 7H), 3.34 (br s,4H), 3.12-3.22 (m, 1H), 2.76-2.86 (m, 1H), 2.63-2.75 (m, 2H), 2.56 (brs, 1H), 2.18 (s, 3H), 1.94 (br s, 1H), 1.77-1.90 (m, 1H).

Example 113:6-(3-methoxy-2-methylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method B

According to Scheme 6, step iii: Example 113 was prepared following thesame procedure described for Example 111, starting from Intermediate 52d(0.2 g, 469.15 μmol) and morpholine (81.74 mg, 938.29 μmol, 82.57 μL) toprovide Example 113 (0.092 g, 212.71 μmol, 45.34% yield) as yellowsolid. ¹H-NMR (400 MHz, CDCl₃) δ 8.45 (br s, 1H), 8.03 (br s, 1H), 7.81(br s, 1H), 7.59 (br s, 1H), 7.23 (br t, J=7.8 Hz, 1H), 6.95-6.81 (m,2H), 3.94 (m, 4H), 3.88 (s, 3H), 3.37 (br s, 4H), 3.25 (br s, 1H), 2.99(m, 1H), 2.92-2.82 (m, 1H), 2.81-2.65 (m, 3H), 2.27 (s, 3H), 2.16 (br s,1H), 1.93-1.90 (m, 1H).

Example 114:6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method B

According to Scheme 6, step iii: Example 114 was prepared following thesame procedure described for Example 111, starting from Intermediate 52b(0.15 g, 365.58 μmol) and morpholine (63.70 mg, 731.16 μmol, 64.34 μL)to provide Example 114 (0.029 g, 66.14 μmol, 18.09% yield) aslight-yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 8.02-7.90(m, 1H), 7.78 (s, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.13-7.01 (m, 3H),3.97-3.87 (m, 4H), 3.40-3.29 (m, 4H), 3.20-3.08 (m, 1H), 2.98 (m, 1H),2.89-2.78 (m, 1H), 2.71 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 2.15-2.10(m, 1H), 1.95-1.82 (m, 1H).

Example 115:6-(2,4-dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method B

According to Scheme 6, step iii: Example 115 was prepared following thesame procedure described for Example 111, starting from Intermediate 52c(0.15 g, 364.70 μmol) and morpholine (63.55 mg, 729.40 μmol, 64.19 μL)to provide Example 115 (0.053 g, 126.95 μmol, 34.81% yield) aslight-yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.48 (s, 2H), 7.69 (s,1H), 7.13-6.99 (m, 3H), 3.97-3.88 (m, 4H), 3.38-3.28 (m, 4H), 3.20-3.08(m, 1H), 2.99 (m, 1H), 2.88-2.75 (m, 1H), 2.70 (m, 2H), 2.35 (s, 3H),2.32 (s, 3H), 2.17-2.05 (m, 1H), 1.95-1.80 (m, 1H).

Example 116:2-(5-(azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method B

According to Scheme 6, step iii: Example 116 was prepared following thesame procedure described for Example 111, starting from Intermediate 52c(0.15, 364.70 μmol) and azetidine (136.48 mg, 1.46 mmol, 161.32 μL) toprovide Example 116 (0.004 g, 9.81 μmol, 2.69% yield) as light-yellowsolid. ¹H-NMR (400 MHz, CDCl₃) δ 8.01 (s, 2H), 7.65 (s, 1H), 7.17-6.99(m, 3H), 4.08 (t, J=7.2 Hz, 4H), 3.12 (m, 1H), 3.02-2.95 (m, 1H),2.83-2.75 (m, 1H), 2.70-2.62 (m, 2H), 2.62-2.52 (m, 2H), 2.35 (s, 3H),2.32 (s, 3H), 2.12-2.06 (m, 1H), 1.92-1.80 (m, 1H).

Example 117:N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,was Prepared According to Scheme 6, Method B

According to Scheme 6, step iii: To a mixture of intermediate 52c (0.1g, 243.13 μmol, 1 eq) and acetamide (28.72 mg, 486.27 μmol, 2 eq) indioxane was added (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (6.92 mg,48.63 μmol, 0.2 eq), CuI (9.24 mg, 48.63 μmol, 0.2 eq) and K₃PO₄ (129mg, 607.82 μmol, 2.5 eq) in one portion at 25° C. under N₂. The mixturewas stirred at 25° C. for 5 min, then heated to 100° C. and stirred for12 hours. The reaction mixture was filtered and the filter wasconcentrated. The residue was further purification by pre-HPLC toprovide Example 117 (0.021 g, 53.92 μmol, 22.18% yield) as a whitesolid. ¹H-NMR (400 MHz, CDCl₃) δ 8.93 (s, 2H), 8.58 (s, 1H), 7.66 (s,1H), 7.03-6.97 (m, 3H), 3.12-3.06 (m, 1H), 2.98-2.88 (m, 1H), 2.82-2.72(m, 1H), 2.72-2.61 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H),2.12-2.05 (m, 1H), 1.88-1.82 (m, 1H).

Example 118:6-(3-methoxy-2-methylphenyl)-2-(5-(2-methoxyethoxy)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method C

According to scheme 6, step iv: To a solution of compound Example 45(150 mg, 411.64 μmol, 1 eq) in DMA (3 mL) was added Cs₂CO₃ (268.24 mg,823.28 μmol, 2 eq) and 1-bromo-2-methoxyethane (572.14 mg, 4.12 mmol,386.58 μL, 10 eq). The mixture was stirred at 20° C. for 12 hours. ThepH of the mixture was adjusted to 7 by the addition of HCl (6 N). Themixture was filtered. The filtrate was concentrated to give the crudeproduct. The crude product was purified by prep-HPLC and Example 118(79.75 mg, 186.50 μmol, 45.31% yield) was obtained as a white solid.¹H-NMR (400 MHz, CDCl₃) δ 8.75 (s, 2H), 7.70 (s, 1H), 7.12 (br d, J=8.4Hz, 1H), 6.77 (s, 1H), 6.72 (m, d, J=8.4 Hz, 1H), 3.80 (s, 3H),3.17-2.96 (m, 2H), 2.87-2.76 (m, 1H), 2.71-2.65 (m, 2H), 2.43 (s, 3H),2.31 (s, 3H), 2.15-2.11 (m, 1H), 1.90-1.85 (m, 1H).

Example 119:2-(5-(2-hydroxyethoxy)pyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method C

According to Scheme 6, step iv: Example 119 was prepared following thesame procedure described for Example 118, starting from Example 45 (150mg, 411.64 μmol) and 2-bromoethan-1-ol (514.40 mg, 4.12 mmol) to provideExample 119 (45.04 mg, 107.73 μmol, 26.17% yield) as a white solid.¹H-NMR (400 MHz, CDCl₃) δ 8.46 (s, 2H), 7.59 (s, 1H), 7.04 (d, J=8.4 Hz,1H), 6.73-6.64 (m, 2H), 3.93 (s, 3H), 3.73 (s, 3H), 3.04-2.97 (m, 2H),2.71-2.46 (m, 3H), 2.23 (s, 3H), 2.08 (m, 1H), 1.80 (m, 1H).

Example 120:6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 7

Intermediate 53:6-(3-bromo-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 2, step viii: To a mixture of intermediate 15b (2 g,5.68 mmol, 1 eq) and 1,3-dibromo-2-methylbenzene (1.42 g, 5.68 mmol,72.57 μL, 1 eq) in dioxane (30 mL) and H₂O (2 mL) were added Pd(dppf)Cl₂(207.76 mg, 283.93 μmol, 0.05 eq) and Na₂CO₃ (1.81 g, 17.04 mmol, 3 eq)in one portion at 25° C. under N₂. The mixture was stirred at 90° C. for12 hours. The residue was poured into ice-water (w/w=1/1) (50 mL). Theaqueous phase was extracted with ethyl acetate (50 mL×3). The combinedorganic phase was washed with brine (50 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo to afford Intermediate 53(1.4 g, 3.54 mmol, 62.37% yield) as a yellow solid. ¹H NMR (CDCl₃, 400MHz) δ 8.92 (d, J=4.8 Hz, 2H), 7.75 (s, 1H), 7.54 (d, J=7.6 Hz, 1H),7.40 (t, J=4.8 Hz, 1H), 7.11-7.06 (m, 2H), 6.24 (s, 1H), 3.00 (t, J=9.6Hz, 2H), 2.64 (t, J=9.6 Hz, 2H), 2.42 (s, 3H).

Intermediate 54:6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-7,8-dihydrophthalazin-1(2H)-one

According to scheme 7, step i: A mixture of intermediate 53 (0.2 g,506.01 μmol, 1 eq) and tributyl(1-ethoxyvinyl)stannane (365.49 mg, 1.01mmol, 341.58 μL, 2 eq) in dioxane (20 mL) was added Pd(PPh₃)₂C₁₂ (17.76mg, 25.30 μmol, 0.05 eq) in one portion at 25° C. under N₂. The mixturewas stirred at 100° C. for 3 hours. HCl (3M; 20 mL) was added to thereaction and stirred 30 min at 25° C., concentrated in vacuo. Theresidue was purified by silica gel chromatography (PE/EtOAc=0/1) toafford intermediate 54 (0.15 g, crude) as yellow solid. ¹H NMR (DMSO-d₆,400 MHz) δ 9.01 (d, J=4.8 Hz, 2H), 7.99 (s, 1H), 7.65-7.75 (m, 1H), 7.36(s, 1H), 6.42 (s, 1H), 2.78-2.87 (m, 2H), 2.60-2.68 (m, 2H), 2.56 (s,3H), 2.36 (s, 3H).

Example 120:6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to scheme 7, step ii: A mixture of intermediate 54 (150.00 mg,418.53 μmol, 1 eq) and ammonium formate (131.96 mg, 2.09 mmol, 5 eq) inEtOH (30 mL) was added Pd/C (0.3 g, 5% purity) under N₂. The mixture wasstirred 16 hours at 25° C. The mixture was filtered, concentrated underreduced pressure and the residue obtained was purified by PREP-HPLC toafford Example 120 (4 mg, 10.86 μmol, 2.60% yield) as a white solid.(DMSO-d₆) δ 9.02 (d, J=4.8 Hz, 2H), 7.85 (s, 1H), 7.71 (br t, J=4.8 Hz,1H), 7.48 (m, 2H), 7.29-7.36 (m, 1H), 3.27 (m, 1H), 2.65-2.95 (m, 4H),2.54 (s, 3H), 2.35 (s, 3H), 1.88-2.03 (m, 2H).

Example 121:6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one,was Prepared According to Scheme 3

Intermediate 19: 3-(2,4-dimethylphenyl)cyclopentan-1-one

According to scheme 3, step i: To a mixture of Rh(COD)Cl₂ (180.17 mg,0.37 mmol) in dioxane (20 mL) and H₂O (4 mL) was added KOH (4.10 g,73.08 mmol). The resulting mixture was stirred at 20° C. under N₂ for0.5 hour. Then to the resulting mixture was added the solution ofcyclopent-2-en-1-one (6.00 g, 73.08 mmol) and(2,4-dimethylphenyl)boronic acid (21.92 g, 146.16 mmol) in dioxane (20mL) dropwise at 20° C. The resulting mixture was stirred at 20° C. for1.5 hours. LCMS showed the desired product. The reaction mixture wasdiluted with 200 mL ethyl acetate and washed by water (60 mL×3). Thenthe organic phase was dried over anhydrous Na₂SO₄ and evaporated invacuo. The residue was purified by column chromatography on silica gel(PE:EtOAc=20:1). The intermediate 19 (11.00 g, 80% yield) was obtainedas a yellow liquid. ¹H NMR (CDCl₃; 400 MHz) δ 7.17-7.10 (m, 1H),7.07-7.02 (m, 2H), 3.67-3.54 (m, 1H), 2.70-2.60 (m, 1H), 2.55-2.45 (m,1H), 2.43-2.39 (m, 1H), 2.381 (s, 3H), 2.37-2.35 (m, 1H), 2.34 (s, 3H),2.31-2.26 (m, 1H), 2.10-1.96 (m, 1H).

Intermediate 20:2-chloro-4-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde

According to scheme 3, step ii: To a mixture of DMF (7.76 g, 106.24mmol, 8.2 mL) in CH₂Cl₂ (100 mL) was added at −20° C. POCl₃ (13.03 g,84.99 mmol, 7.9 mL). Then the mixture was stirred at 0° C. for 1 hours.Then to the mixture was added a solution of intermediate 19 (10.00 g,53.12 mmol) in CH₂Cl₂ (20 mL) at −20° C. The reaction was stirred at 0°C. for 2 hours. Then the reaction was stirred at 25° C. for 12 hours.LCMS showed the reaction was finished. The reaction was quenched withwater (100 mL) at 0° C. Then the mixture was extracted with CH₂Cl₂ (100mL×3). The combined organic layer was dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated. The residue was purified bychromatography on silica gel (PE:EtOAc=10:1) The mixture of2-chloro-4-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde 20 and itsregioisomer2-chloro-5-(2,4-dimethylphenyl)cyclopent-1-ene-1-carbaldehyde 20′ (3.00g, 24% yield) was obtained as a yellow oil which was engaged in the nextstep.

Intermediate 21: ethyl4-(2,4-dimethylphenyl)-2-formylcyclopent-1-ene-1-carboxylate

To a mixture of intermediates 20 and 20′ (1.5 g, 6.39 mmol) and Et₃N(1.29 g, 12.78 mmol, 1.77 mL) in EtOH (40 mL) was added Pd(dppf)Cl₂(467.61 mg, 0.64 mmol) at 25° C. under N₂ protection. The suspension wasdegassed under vacuo and purged with CO several times. The mixture wasstirred under CO (3 Mpa) at 120° C. for 12 hours. Then the reactionmixture was concentrated. The crude mixture of intermediates 21 and itsregioisomer 21′ (1.5 g, crude) was obtained as black solid and engagedin the next step.

Example 121:6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one

To a mixture of intermediates 21 and its regioisomer 21′ (3.00 g, 11.02mmol) and 2-pyridylhydrazine (2.41 g, 16.53 mmol HCl) in toluene (100mL) was added TsOH (1.90 g, 11.02 mmol) at 25° C. under N₂. The mixturewas stirred at 120° C. for 48 hours. The reaction mixture wasconcentrated. The residue was purified by chromatography on silica gel(PE/EtOAc=3:1) to give a crude product which was further purified byprep-HPLC. Example 121 (180 mg, 5% yield) was obtained as a yellow oil.¹H-NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 8.10-7.96 (m, 2H), 7.90-7.80 (m,1H), 7.55-7.45 (m, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.07-6.99 (m, 2H),4.10-3.99 (m, 1H), 3.50-3.37 (m, 2H), 3.06-3.01 (m, 2H), 2.38 (s, 3H),2.33 (s, 3H).

Example 122:7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one,was Prepared According to Scheme 4

Intermediate 31: 2′,4′-dimethyl-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one

According to scheme 4, step i: A solution of cyclohex-2-en-1-one (3.50g, 36.41 mmol, 1.00 eq), 1-iodo-2,4-dimethylbenzene (10.81 g, 46.60mmol, 1.28 eq), Na₂CO₃ (6.04 g, 72.82 mmol, 2.00 eq), Pd(PPh₃)₂Cl₂ (2.56g, 3.64 mmol, 0.10 eq), XPhos (2.08 g, 4.37 mmol, 0.12 eq) in DMSO(100.00 mL) was stirred at 100° C. under N₂ atmosphere for 2 hours. LCMSshowed the desired product and the reaction was finished. The reactionmixture was diluted with ethyl acetate (100 mL) and washed with H₂O (40mL×3). The organic layers dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was purified by columnchromatography (PE:EtOAc=5:1). Intermediate 31 (1.60 g, 7.99 mmol, 22%yield) was obtained as a brown liquid. ¹H NMR (CDCl₃; 400 MHz) δ7.19-6.94 (m, 3H), 5.92-5.90 (m, 1H), 2.53-2.50 (m, 2H), 2.45-2.40 (m,2H), 2.26 (s, 3H), 2.21 (s, 3H), 2.09-2.05 (m, 2H).

Intermediate 33: ethyl2′,4′-dimethyl-5-oxo-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-carboxylate

According to scheme 4, step iii: To a solution of intermediate 31 (2.40g, 11.98 mmol, 1.00 eq) in THF (60.00 mL) at −78° C. was added LDA (2 M,8.99 mL, 1.50 eq) dropwise. The resulting mixture was stirred at −78° C.for 1 hours. To the reaction mixture was added cyano ethyl acetate (1.66g, 16.77 mmol, 1.65 mL, 1.40 eq) at −78° C. dropwise and stirred for 4hours. The reaction mixture was quenched with NH₄Cl aqueous (20 mL) andextracted with ethyl acetate 150 mL The combined organic layers werewashed with H₂O 100 mL, dried over Na₂SO₄ filtered and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography (PE:EtOAc=5:1). Intermediate 33 (2.10 g, 7.71 mmol,64.37% yield) was obtained as a yellow oil. ¹H NMR (CDCl₃; 400 MHz) δ7.04-7.04 (m, 3H), 6.09-6.05 (m, 1H), 4.25-4.3 (m, 2H), 2.73-2.53 (m,4H), 2.35 (s, 3H), 2.30 (s, 3H) 1.66-1.60 (m, 3H).

Intermediate 34: ethyl4-(2,4-dimethylphenyl)-2-oxocyclohexane-1-carboxylate

According to scheme 4, step ii: A solution of Intermediate 33 (1.40 g,5.14 mmol, 1.00 eq) in MeOH (20.00 mL) was added Pd/C (500 mg, 10%purity) under N₂ atmosphere. The suspension was degassed in vacuo andpurged with H₂ several times. The mixture was stirred under H₂ (50 psi)at 20° C. for 16 hours. The reaction mixture was filtered andconcentrated under reduced pressure. The crude product was purified byflash silica gel chromatography (PE:EtOAc=10:1). Intermediate 34 (500.00mg, 1.82 mmol, 35.40% yield) has been obtained as a yellow oil

Intermediate 35:7-(2,4-dimethylphenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

According to scheme 4, step iv: The mixture of Intermediate 34 (200 mg,729.00 μmol, 1.00 eq), K₂CO₃ (403.02 mg, 2.92 mmol, 4.00 eq) andformimidamide (113.84 mg, 1.09 mmol, 1.50 eq) in EtOH (8.00 mL) wasstirred at 90° C. for 3 hours. The reaction mixture was concentrated andthe residue was diluted with ethyl acetate (100 ml). The solution waswashed with H₂O (40 mL×3). The organic phase was dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo. The Intermediate 35 (120.00mg, 471.83 μmol, 65% yield) was obtained as a light-yellow solid. ¹H NMR(DMSO-d₆; 400 MHz) δ 12.30 (s, 1H), 7.99 (s, 1H), 7.17-7.11 (m, 1H),6.97-6.99 (m, 1H), 3.11-3.08 (m, 1H), 2.68-2.39 (m, 4H), 2.28 (s, 3H),2.24 (s, 3H), 1.86-1.84 (m, 2H), 1.75-1.1.72 (m, 2H).

Example 122:7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

According to scheme 4, step v: The mixture of intermediate 35 (100.00mg, 393.19 μmol, 1.00 eq), 2-bromopyridine (80.76 mg, 511.15 μmol, 1.30eq), CuI (7.49 mg, 39.32 μmol, 0.10 eq), 1,10-phenanthroline (14.17 mg,78.64 μmol, 0.20 eq) and KOH (44.12 mg, 786.38 μmol, 2.00 eq) in DMF(4.00 mL) was stirred at 100° C. for 12 hours under N₂ atmosphere. Thereaction mixture was diluted with 100 mL ethyl acetate and washed bywater (30 mL×3). The organic phase was dried over Na₂SO₄, evaporated invacuo. The crude product was purified by prep-HPLC (formic acid asadditive). Example 122 (45.00 mg, 135.78 μmol, 34.53% yield) wasobtained as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.66-8.65 (m,1H), 8.48 (s, 1H), 8.06-8.04 (m, 1H), 7.77-7.75 (m, 1H), 7.59-7.55 (m,1H), 7.18-7.15 (m, 1H), 7.02-6.99 (m, 1H), 3.16-3.14 (m, 1H), 2.75-2.66(m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.94-1.921 (m, 1H), 1.83-1.81 (m,2H).

Example 124:6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

To a mixture of Example 92 (50.0 mg, 130 μmol, 1.00 eq) in DCM (2.00 mL)was added MnO₂ (113 mg, 1.30 mmol, 10.0 eq) at 25° C. The mixture wasstirred at 25° C. for 23 h. The reaction was filtered and concentrated.The residue was purified by column chromatography (SiO₂, PE/EtOAc=1/1 to0:1, Rf=0.48) to give Example 124 (37.0 mg, 94.7 μmol) as a green solid.¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.8 Hz, 2H), 7.71 (s, 1H), 7.51 (d,J=8.2 Hz, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.18 (d,J=3.4 Hz, 1H), 6.99 (d, J=7.4 Hz, 1H), 6.50 (d, J=3.4 Hz, 1H), 3.48-3.33(m, 2H), 3.07-2.87 (m, 3H), 2.80-2.66 (m, 1H), 2.37-2.28 (m, 1H),2.14-2.06 (m, 1H), 1.11-1.02 (m, 4H).

Example 125:2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was Prepared According to Scheme 6, Method A

Intermediate 52e:2-(5-bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step i: Intermediate 52e was prepared followingthe same procedure described for intermediate 52a, starting fromIntermediate 7b (500 mg, 1.85 mmol) and 2,5-dibromopyridine (527.98 mg,2.22 mmol), to provide intermediate 52e (0.5 g, 1.01 mmol, 54.41% yield)as red solid. m/z (M+H)⁺=427.0, 429.0.

Example 125:2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 6, step ii: Example 125 was prepared following thesame procedure described for Example 107, starting from Intermediate 52e(180 mg, 421.26 μmol) and cyclopropylboronic acid (72.37 mg, 842.51μmol), to provide Example 125 (14.61 mg, 37.35 μmol, 8.87% yield) as alight pink solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 2H), 7.83 (s,1H), 7.18 (t, J=7.97 Hz, 1H), 6.90 (d, J=7.65 Hz, 1H), 6.86 (d, J=8.16Hz, 1H), 3.79 (s, 3H), 3.13-3.24 (m, 1H), 2.64-2.85 (m, 3H), 2.57 (br s,1H), 2.18 (s, 3H), 2.04-2.12 (m, 1H), 1.94 (br s, 1H), 1.78-1.90 (m,1H), 1.08-1.18 (m, 2H), 0.90-1.01 (m, 2H).

Example 126:2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,was prepared according to scheme 1, Method B

Intermediate 6f:5-(3-cyclopropoxy-2-methylphenyl)-3-methoxy-4,5,6,7-tetrahydroisobenzofuran-1(3H)-one

According to Scheme 1 Step i to v: Intermediate 6f was preparedsimilarly to intermediate 6a in Example 1, starting from1-bromo-3-cyclopropoxy-2-methylbenzene, and was obtained with an overallyield of 6% as a colorless oil. m/z (M+H)⁺=315.3.

Intermediate 7d:6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 1 Step vii: Intermediate 7b was prepared similarlyto intermediate 7a in Example 6, starting from Intermediate 6f (1.77 g,5.60 mmol), to provide Intermediate 7d (1.52 g, 4.56 mmol, 81.5% yield)as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (br s, 1H),7.56 (s, 1H), 7.22-7.11 (m, 2H), 6.84 (d, J=7.4 Hz, 1H), 3.77-3.70 (m,1H), 3.22-3.11 (m, 1H), 2.99-2.88 (m, 1H), 2.81-2.71 (m, 1H), 2.71-2.54(m, 2H), 2.18 (s, 3H), 2.15-2.08 (m, 1H), 1.92-1.80 (m, 1H), 0.82-0.77(m, 4H).

Example 126:2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

According to Scheme 1 Step viii: Example 126 was prepared as per Example6, starting from intermediate 7d (1.00 g, 3.00 mmol) and2,5-dibromopyrimidine (856 mg, 3.60 mmol), to provide Example 126 (0.74g, 1.52 mmol, 50.7% yield) as red solid. ¹H NMR (400 MHz, CDCl₃) δ 8.95(s, 2H), 7.69 (s, 1H), 7.24-7.14 (m, 2H), 6.85 (d, J=7.6 Hz, 1H),3.77-3.70 (m, 1H), 3.20 (br s, 1H), 3.00 (br d, J=16.3 Hz, 1H),2.86-2.78 (m, 1H), 2.70 (br dd, J=9.2, 16.8 Hz, 2H), 2.20-2.18 (m, 3H),2.13 (br s, 1H), 1.94-1.85 (m, 1H), 0.82-0.77 (m, 4H).

Example 127:N-(2-(6-(3-cyclopropoxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,was Prepared According to Scheme 6, Method B

According to Scheme 6, step iii: Example 127 was prepared as per Example117, starting from Example 126 (0.85 g, 1.88 mmol) and acetamide (222mg, 3.75 mmol), to provide Example 127 (242 mg, 558.61 μmol, 29.79%yield) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.07-9.00 (m,1H), 8.97 (s, 2H), 7.76 (s, 1H), 7.24-7.15 (m, 2H), 6.86 (br d, J=7.4Hz, 1H), 3.75 (br s, 1H), 3.25 (br s, 1H), 3.00 (br d, J=19.4 Hz, 1H),2.92-2.82 (m, 1H), 2.82-2.64 (m, 2H), 2.20 (s, 6H), 2.17-2.13 (m, 1H),1.93 (br d, J=7.2 Hz, 1H), 0.80 (br s, 4H).

Example 128:(+6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneand EXAMPLE 129:(+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The enantiomers constituting racemic Example 104 (483 mg) were separatedby preparative SFC to give(−)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 128 (188 mg, 39%) with an enantiomeric excess of 100%, and(+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 129 (199 mg, 41%) with an enantiomeric excess of 99.9%, both aswhite solid.

Example 128: ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.4 Hz, 2H), 7.70 (s,1H), 7.42 (t, J=4.8 Hz, 1H), 7.28-7.15 (m, 2H), 6.85 (d, J=7.6 Hz, 1H),3.75 (tt, J=6.0, 3.2 Hz, 1H), 3.25-3.17 (m, 1H), 3.05-2.95 (m, 1H),2.87-2.76 (m, 1H), 2.75-2.60 (m, 2H), 2.20-2.10 (m, 1H), 1.95-1.83 (m,1H), 0.85-0.75 (m, 4H).

Example 129: ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.4 Hz, 2H), 7.70 (s,1H), 7.42 (t, J=4.8 Hz, 1H), 7.25-7.15 (m, 2H), 6.86 (d, J=7.6 Hz, 1H),3.75 (tt, J=6.0, 3.2 Hz, 1H), 3.25-3.17 (m, 1H), 3.05-2.95 (m, 1H),2.83-2.76 (m, 1H), 2.75-2.60 (m, 2H), 2.20-2.07 (m, 1H), 1.95-1.82 (m,1H), 0.85-0.75 (m, 4H).

Example 130:(+6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneand EXAMPLE 131:(+)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The enantiomers constituting racemic Example 91 (505 mg) were separatedby preparative SFC to give(−)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 130 (187 mg, 37%) with an enantiomeric excess of 99.6%, and(+)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 131 (187 mg, 37%) with an enantiomeric excess of 99.9%, both aswhite solid.

Example 130: ¹H-NMR (400 MHz, CDCl₃) δ 8.93 (d, J=4.4 Hz, 2H), 7.70 (s,1H), 7.42 (t, J=4.8 Hz, 1H), 7.26-7.23 (m, 2H), 6.92-6.87 (m, 1H), 3.83(tt, J=6.0, 3.2 Hz, 1H), 3.59-3.49 (m, 1H), 3.05-2.92 (m, 2H), 2.76-2.58(m, 2H), 2.23-2.14 (m, 1H), 1.99-1.85 (m, 1H), 0.90-0.83 (m, 4H).

Example 131: ¹H-NMR (400 MHz, CDCl₃) δ 8.93 (d, J=4.8 Hz, 2H), 7.70 (s,1H), 7.45-7.39 (m, 1H), 7.26-7.23 (m, 2H), 6.94-6.86 (m, 1H), 3.83 (tt,J=3.2, 6.0 Hz, 1H), 3.63-3.45 (m, 1H), 3.04-2.91 (m, 2H), 2.77-2.57 (m,2H), 2.23-2.13 (m, 1H), 1.99-1.85 (m, 1H), 0.92-0.79 (m, 4H).

Example 132:(−)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneand Example 133:(+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The enantiomers constituting racemic Example 93 (488 mg) were separatedby preparative SFC to give(+6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 132 (232 mg, 48%) with an enantiomeric excess of 100%, and(+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 133 (210 mg, 43%) with an enantiomeric excess of 100%, both aswhite solid.

Example 132: ¹H-NMR (400 MHz, CDCl₃) δ 8.74 (s, 2H), 7.68 (s, 1H),7.25-7.15 (m, 2H), 6.85 (d, J=6.4 Hz, 1H), 3.74 (tt, J=6.0, 3.2 Hz, 1H),3.26-3.17 (m, 1H), 3.05-2.95 (m, 1H), 2.85-2.77 (m, 1H), 2.75-2.60 (m,2H), 2.43 (s, 3H), 2.18-2.10 (m, 1H), 1.95-1.83 (m, 1H), 0.85-0.78 (m,4H).

Example 133: ¹H-NMR (400 MHz, CDCl₃) δ 8.74 (s, 2H), 7.68 (s, 1H),7.23-7.15 (m, 2H), 6.85 (d, J=6.4 Hz, 1H), 3.74 (tt, J=6.0, 3.2 Hz, 1H),3.25-3.16 (m, 1H), 3.05-2.95 (m, 1H), 2.85-2.77 (m, 1H), 2.75-2.60 (m,2H), 2.43 (s, 3H), 2.18-2.07 (m, 1H), 1.95-1.83 (m, 1H), 0.83-0.76 (m,4H).

Example 134:(+6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneand EXAMPLE 135:(+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The enantiomers constituting racemic Example 94 (493 mg) were separatedby preparative SFC to give(−)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 134 (218 mg, 48%) with an enantiomeric excess of 100%, and(+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 135 (215 mg, 43%) with an enantiomeric excess of 99.9%, both aswhite solid.

Example 134: ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 2H), 7.69 (s, 1H),7.30-7.25 (m, 1H), 6.90-6.86 (m, 2H), 3.94 (s, 3H), 3.56-3.53 (m, 1H),3.04-2.93 (m, 2H), 2.75-2.57 (m, 2H), 2.42 (s, 3H), 2.20-2.15 (m, 1H),1.93-1.85 (m, 1H).

Example 135: ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 2H), 7.69 (s, 1H),7.27-7.22 (m, 1H), 6.90-6.86 (m, 2H), 3.93 (s, 3H), 3.56-3.53 (m, 1H),3.04-2.93 (m, 2H), 2.75-2.57 (m, 2H), 2.42 (s, 3H), 2.23-2.15 (m, 1H),1.93-1.85 (m, 1H).

Example 136:(−)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamideand Example 137:(+)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide

The enantiomers constituting racemic Example 117 (610 mg) were separatedby preparative SFC to give(−)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamideExample 136 (187 mg, 31%) with an enantiomeric excess of 99.4%, and(+)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamideExample 137 (218 mg, 36%) with an enantiomeric excess of 100%, both asyellow solid.

Example 136: ¹H-NMR (400 MHz, CDCl₃) δ 8.99 (s, 1H), 7.76 (s, 1H),7.12-7.05 (m, 3H), 3.17-2.70 (m, 5H), 2.37 (s, 3H), 2.33 (s, 3H),2.22-2.18 (m, 4H), 1.97-1.90 (m, 1H).

Example 137: ¹H-NMR (400 MHz, CDCl₃) δ=8.90 (s, 1H), 7.76 (s, 1H),7.04-6.97 (m, 3H), 3.10-2.62 (m, 5H), 2.29 (s, 3H), 2.25 (s, 3H),2.10-2.09 (m, 4H), 1.87-1.83 (m, 1H).

Example 138:(+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneand Example 139:(+6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one

The enantiomers constituting racemic Example 124 (440 mg) were separatedby preparative SFC to give(+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 138 (140 mg, 32%) with an enantiomeric excess of 99.5%, and(−)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-oneExample 139 (155 mg, 35%) with an enantiomeric excess of 98.9%, both asyellow solid.

Example 138: ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.9 Hz, 2H), 7.71 (s,1H), 7.52 (d, J=8.2 Hz, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.24 (t, J=7.7 Hz,1H), 7.18 (d, J=3.3 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.50 (d, J=3.2 Hz,1H), 3.42-3.37 (m, 2H), 3.04-2.96 (m, 3H), 2.93-2.73 (m, 1H), 2.32 (brd, J=11.7 Hz, 1H), 2.10-2.06 (m, 1H), 1.12-1.02 (m, 4H).

Example 139: ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (d, J=4.9 Hz, 2H), 7.71 (s,1H), 7.52 (d, J=8.2 Hz, 1H), 7.42 (t, J=4.8 Hz, 1H), 7.24 (t, J=7.7 Hz,1H), 7.18 (d, J=3.3 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.50 (s, 1H),3.50-3.38 (m, 2H), 3.03-2.93 (m, 3H), 2.88-2.73 (m, 1H), 2.30 (br d,J=11.7 Hz, 1H), 2.09-2.03 (m, 1H), 1.10-1.04 (m, 4H).

C. Analytical Part Melting Points:

Values are peak values and are obtained with experimental uncertaintiesthat are commonly associated with this analytical method. For a numberof compounds, melting points were determined in open capillary tubes ona YRT-3 apparatus. Melting points were measured with a temperaturegradient of 1.5° C./minute. Maximum temperature was 270° C. The meltingpoint was read from a digital display. For some compounds, DSC methodwas used according to the following conditions.

DSC conditions Instrument: NETZSCH DSC214 Crucible Pan Al, pierced lidProtect flow N₂ 60 mL/min Purge flow N₂ 40 mL/min Gradient Ratio: 50° C.to 350° C.; 10° C./min

LCMS Methods:

The High-Performance Liquid Chromatography (HPLC) measurement wasperformed using a LC pump, a diode-array or a UV detector. Flow from thecolumn was brought to the Mass Spectrometer (MS) which was configuredwith an atmospheric pressure ion source. It is within the knowledge ofthe skilled person to set the tune parameters in order to obtain ionsallowing the identification of the compound's nominal monoisotopicmolecular weight (MW) and/or exact mass monoisotopic molecular weight.Data acquisition was performed with appropriate software. ES MS detectorwas used, acquiring both in positive and negative ionization modes.Compounds can be described by their molecular ion corresponding to the[M+H] (protonated molecule) and/or [M−H] (deprotonated molecule). Formolecules with multiple isotopic patterns (Br, Cl), the reported valueis the one obtained for the lowest isotope mass. All results wereobtained with experimental uncertainties that are commonly associatedwith the method used.

NMR:

¹H NMR spectra were recorded on a Varian 400 MHz spectrometer. Chemicalshifts are expressed in parts per million (ppm, δ units). Splittingpatterns describe apparent multiplicities and are designated as s(singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), br(broad).

SFC-MS:

Preparative Chiral separation were performed using a preparativeinstrument equipped with Waters 2998 PDA detector. Specific methods usedare described herebelow and results are reported in table 1.

Methods Method C1 Method C2 Instrument: Thar SFC80 preparative SFC MGpreparative SFC Column: Chiralcel OJ 250 * 25 mm ChiralPak AD, 250 ×i.d. 10 μm 30 mm i.d., 5 μm Column 40° C. 38° C. temperature: A for CO2and B for 2-propanol A for CO₂ and B Mobile phase (0.1% NH₃H₂O) for ETOH(0.1% NH₃H₂O) Flow rate: 70 mL/min 60 mL/min Gradient B = 40% B = 40%Detection: 220 nm 220 nm System back 100 bar 100 bar pressure Cycle time7 min 4-15 min

Optical Rotations:

Optical rotations were measured on a Rudolph AUTOPOL V polarimeter usinga sodium lamp (589 nm), at a concentration of 10 mg/mL, in methanol orchloroform as solvent, at a temperature of 20° C. The sign of therotation (+ or −) is given and is reported using degrees in Table 1.

TABLE 1 Analytical data for individual optical isomers. SFC RT Ex. (min)SFC method [α _(D)] (°) Solvent 4 4.94 C1 −58.03° MeOH 5 5.80 C1 +56.91°MeOH 128 4.11 C2 −32.18° MeOH 129 4.62 C2 +29.03° MeOH 130 2.24 C2−28.98° MeOH 131 2.56 C2 +29.76° MeOH 132 4.74 C2 −26.94° MeOH 133 5.59C2 +31.70° MeOH 134 2.20 C2 −44.55° MeOH 135 2.53 C2 +27.48° MeOH 1361.24 C2 −50.51° CHCl₃ 137 1.99 C2 +43.53° CHCl₃ 138 1.73 C2 +7.42° CHCl₃139 1.86 C2 −8.27° CHCl₃

In Vitro Pharmacology

Compounds of Formula (I), (II) and (III) are antagonists or negativeallosteric modulators of the mGluR7 as they reduce or inhibit the mGluR7response induced by glutamate or a mGluR7 agonist, such as L-AP4.

The methods described below are suitable for the characterization ofsuch compounds, and more particularly the compounds according to Formula(I), are described below.

Inositol Monophosphate Production Assay (IP1 Assay): MembranePreparation and Protocol:

HEK293 cells were transiently transfected with mGluR7 by electroporationand seeded in a poly-ornithine coated 96-well plate at the density of150 000 cells/well. To allow the monitoring of receptor activity throughmeasurements of inositol monophosphate (IP1) production, mGluR7 wastransfected with a chimeric Gq/Gi protein (Gqtop). and was alsoco-transfected with EAAC1, a glutamate transporter, to avoid influenceof extracellular glutamate. Cells were cultured in Dulbecco's ModifiedEagle Medium (DMEM, Invitrogen, Cergy Pontoise, France), supplementedwith 10% of Fetal Bovine Serum (FBS). Medium was changed by Glutamax™(Invitrogen, Cergy Pontoise, France) to reduce extracellular glutamateconcentration 3 hours before stimulation

The HTRF-based assays from CisBio Bioassays allow the measure ofdifferent cell signaling pathways, notably those allowing thedetermination of the production of the second messenger inositolphosphate (IP). IP1 production was determined using the IP-One HTRF kit(CisBio Bioassays), a competitive immunoassay using cryptate-labeledanti-IP1 antibody and d2-labeled IP, according to the manufacturer'srecommendations. All points were realized in triplicate.

Data Analysis

Data were analyzed with Prism 6 software (GraphPadSoftware, San Diego,Calif.). Typically, in each experiment, a four-parameterconcentration-response curve equation was used to fit data and potency(IC₅₀) is estimated as logarithms (log IC₅₀). Data were calculated as %of the control mGluR7 agonist L-AP4 response, defined as the responsethat is generated upon addition of an EC₈₀-equivalent concentration ofL-AP4.

Results:

The Table 2 below represents the mean IC₅₀ obtained from at least twoindependent experiments.

TABLE 2 Pharmacological activity for compounds according to theinvention. human mGluR7 Example IC₅₀ (nM)* 1 +++ 2 ++ 3 + 4 + 5 +++ 6+++ 7 +++ 8 +++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++17 +++ 18 +++ 19 +++ 20 +++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27+++ 28 +++ 29 +++ 30 +++ 32 ++ 33 +++ 34 + 35 +++ 36 + 37 +++ 38 +++ 39+++ 40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 ++ 49 +++50 +++ 51 +++ 52 +++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 +++ 59 +++ 60+++ 61 +++ 63 ++ 64 + 65 ++ 66 +++ 67 ++ 68 ++ 69 +++ 70 ++ 71 ++ 72 +++73 + 74 +++ 75 +++ 76 +++ 77 +++ 78 +++ 79 +++ 80 +++ 81 ++ 82 ++ 83 ++84 +++ 85 +++ 86 ++ 87 +++ 88 + 89 +++ 90 +++ 91 +++ 92 +++ 93 +++ 94+++ 95 +++ 96 +++ 97 +++ 98 +++ 99 + 100 +++ 101 +++ 102 ++ 103 + 104+++ 105 + 106 + 107 ++ 108 +++ 109 +++ 110 +++ 111 + 112 +++ 113 +++ 114+++ 115 +++ 116 +++ 117 +++ 118 +++ 119 +++ 120 + 121 + 122 +++ 124 +++125 +++ 126 +++ 127 +++ 128 +++ 129 ++ 130 +++ 131 +++ 132 +++ 133 + 134+++ 135 ++ 136 + 137 +++ 138 ++ 139 +++ * Table legend: (+): 1 μM < IC₅₀<30 μM (++): 500 nM < IC₅₀ < 1 μM (+++): IC₅₀ < 500 nM

In Vivo Pharmacology

Compounds of Formula (I), (II) and (III) are antagonists or negativeallosteric modulators of the mGluR7 and can exert an in vivopharmacological activity in disease models associated with glutamatedysfunction.

The pharmacological models suitable for the characterization of theefficacy of such compounds in various indications can be, but are notlimited to, the animal models described below. The person skilled in theart will recognize that alternative models for disorders describedherein exist and can be used, and that these evolve with medical andscientific progresses.

Elevated-plus-maze (EPM) model of anxiety in rodent: The test can becarried out as described by Pellow et al. (J Neurosci Methods (1985),149) and File et al. (Psychopharmacol. (1993), 491). The apparatusconsists of a gray PVC cross-shaped maze, elevated from the floor. Itpossesses two opposite open arms and two opposite enclosed arms of thesame size, but with walls. The central square formed by the arms isopen. The apparatus is placed in a weakly illuminated room. Sixtyminutes after the end of the second stress session, each animal isplaced in the central square of the plus-maze, facing an enclosed arm.They are then be allowed to freely explore the maze during the 5-mintest. The maze is cleaned with water between each animal in order toavoid odor trails left by the animals. During the EPM test, thefollowing parameters are measured: time spent on open arms (TO), timespent in closed arms (TC), number of entries into open arms (EO), numberof entries into closed arms (EC). Two parameters are calculated: Timeratio (% of time spent on open arms)=TO/TO+TC; Entries ratio (% entriesinto open arms)=EO/EO+EC. An entry is defined as all four paws in thearm. Compound of Formula (I), (II) and (III) may be administered 30 minto 2 h (depending of its pharmacokinetic properties) prior to EPM test.

Fear Conditioning Model of Post-Traumatic Stress Disorder in the Rat:

The experiment can take place in one compartment of an active avoidancecage (or shuttle box), with a grid floor controlled by a personalcomputer and that can deliver foot shocks. The test shall be performedin 2 phases (conditioning and testing) spaced by 24 hours. The Phase 1(named conditioning) consists of a background white noise (63 dB)produced in the chamber during the entire experiment. The conditioningsession lasts 5 minutes and 30 s. The rats is placed in the chamber fora 2-min acclimation, then four 1 s-footshocks (0.5 mA) are deliveredwith a 60 s interval between shocks. Thirty seconds after the lastshock, the rat is removed from the chamber before being placed back inits home cage. The Phase 2 (testing) takes place 24 h afterconditioning. The rats are placed back in the chamber and their freezingbehaviour is recorded for 5 min. The total time spent by the rat infreezing behaviour, the beginning time and the duration of each episodeof freezing during the 5-min testing session are the experimentalparameters. Compound of Formula (I), (II) and (III) may be administered30 min to 2 h (depending of its pharmacokinetic properties) before thetest session.

Novel-object recognition test of cognitive deficit in mice: Theexperiment can be performed according to Nilsson et al. (2007) withminor modifications (Wozniak et al., 2016). Following a 2-dayhabituation period (10 min/day), a training trial is performed, wheremice are allowed to explore two identical objects for 5 min. About 1 hlater, a test trial is conducted, where one of the familiar objects isreplaced by a novel object. The animals are then allowed to explore theobjects for 5 min. Compound of Formula (I), (II) and (III) may beadministered 30 min to 2 h (depending of its pharmacokinetic properties)before MK-801 (0.3 mg/kg) which is administered 30 min before thetraining trial. Time spend exploring (i.e., sniffing or touching) thefamiliar (Tfamiliar) or novel object (Tnovel) is measured by a trainedobserver and then the recognition index is calculated for each mouse[(Tnovel−Tfamiliar)/(Tfamiliar+Tnovel)]×100.

Prepulse inhibition (PPI) test of schizophrenia in rodent: The procedurecan be performed according to Czyrak et al. (2003). On the day beforethe experiment, the animals are subjected to a single startle sessionconsisting of two trials, each presented 20 times during the session.During the first trial, a 120 dB, 40 ms pulse is presented, and on thesecond trial this pulse is preceded by a 75 dB, 20 ms prepulse. On theday of the experiment, the animals are habituated to the backgroundwhite noise (65 dB) for 5 min (which continued throughout the test),after that the startle session is carried out as described above.Startle response amplitude is defined as the difference between themaximum force detected during a recording window and the force measuredimmediately before the stimulus onset (the threshold is set at 10 g).

For each animal, the amplitudes are averaged separately for each type oftrial. The PPI is calculated as the difference between the amplitudes ofthe pulse (P) and the prepulse+pulse (PP+P), divided by the amplitude ofthe pulse alone [([P−(PP+P)]/P)×100]. Compound of Formula (I), (II) and(III) may be administered 30 min to 2 h (depending of itspharmacolkinetic properties) prior to MK-801 (0.3 mg/kg), which wasadministered 30 min before the habituation phase.

Noise-Induced Hearing Loss Model in the Mice:

Groups of 3-4-month-old CBA/CaJ mice undergo baseline testing (auditorybrainstrem response (ABR) audiograms, Distorsion Product of AutoacousticEmissions (DPOAE)) followed by loud noise exposure comprised of an 8-16kHz octave band of noise at 110 to 120 dB Sound Pressure Level (SPL)(preferably 110 db SPL) for a period ranging from 30 min to 2 hours(preferably 45 min). Such noise trauma protocol has consistently beenshown to produce 25-35 dB threshold shift in CBA mice (Kujawa andLiberman, 2009). Compound of Formula (I), (II) and (III) may beadministered 30 min to 2 h (depending of its pharmacokinetic properties)prior to noise exposure, and or after noise exposure. Hearing functionis measured at different timepoint, for example 24 hours, 2 and 4 weekspost-acoustic trauma. The experimental groups is compared to the controlgroup through the measure of, for example, ABR Threshold, or ABRThreshold shift.

Colorectal Distension test of visceral pain in rat. The procedure can beperformed according to Moloney et al. (Neurobiol of Stress (2015), 28).,Animals are fasted overnight (16 h) and on the day of testing, areanaesthetised with isoflurane and a 6 cm latex balloon is inserted intothe colorectal cavity, 1 cm from the anus. The animals are allowed torecover for 20 min before colorectal distension commenced. The paradigmused is an ascending phasic distension from 0 mmHg to 80 mmHg over 8 minusing a computer-driven electronic barostat. The parameters measured arethe threshold pressure (mmHg) that evokes visually identifiable visceralpain behavior, and the total number of pain behaviours. Postures definedas visceral pain behaviours are abdominal retractions and/or abdominalwithdrawal reflex. Compound of Formula (I), (II) and (III) may beadministered 30 min to 2 h (depending of its pharmacokinetic properties)prior to colorectal distension (T0). Animals undergo the ballooninsertion protocol 10 min later (T10) and are allowed to recover untilT30. Visceral pain behaviours are assessed at T30 and immediately after,the animals are euthanized.

Formulation Examples

The compounds according to the invention may be provided in an aqueousphysiological buffer solution for parenteral administration.

The compounds of the present invention are also capable of beingadministered in unit dose forms, wherein the expression “unit dose”means a single dose which is capable of being administered to a patient,and which can be readily handled and packaged, remaining as a physicallyand chemically stable unit dose comprising either the active compounditself, or as a pharmaceutically acceptable composition, as describedhereinafter. Compounds provided herein can be formulated intopharmaceutical compositions by mixture with one or more pharmaceuticallyacceptable excipients. Such unit dose compositions may be prepared foruse by oral administration, particularly in the form of tablets, simplecapsules or soft gel capsules; or intranasally, particularly in the formof powders, nasal drops, or aerosols; or dermally, for example,topically in ointments, creams, lotions, gels or sprays, or viatrans-dermal patches; or by injection into the inner ear and/or into themiddle ear (e.g. transtympanic injection), preferably by injection intothe middle ear using sustained release system as for example transportenhancers (e.g. hyaluronic acid, DMSO), tixotropic or thermogelingformulation to enable a painless administration and forming a gel or ahigh viscous composition ensuring prolonged and continuous release ofthe active ingredient.

The compositions may conveniently be administered in unit dosage formand may be prepared by any of the methods well-known in thepharmaceutical art, for example, as described in Remington: The Scienceand Practice of Pharmacy, 20th ed.; Gennaro, A. R., Ed.; LippincottWilliams & Wilkins: Philadelphia, Pa., 2000.

Preferred formulations include pharmaceutical compositions in which acompound of the present invention is formulated for oral or parenteraladministration.

For oral administration, tablets, pills, powders, capsules, troches andthe like can contain one or more of any of the following ingredients, orcompounds of a similar nature: a binder such as microcrystallinecellulose, or gum tragacanth; a diluent such as starch or lactose; adisintegrant such as starch and cellulose derivatives; a lubricant suchas magnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, or methyl salicylate. Capsules can be in the form of ahard capsule or soft capsule, which are generally made from gelatinblends optionally blended with plasticizers, as well as a starchcapsule. In addition, dosage unit forms can contain various othermaterials that modify the physical form of the dosage unit, for example,coatings of sugar, shellac, or enteric agents. Other oral dosage formssyrup or elixir may contain sweetening agents, preservatives, dyes,colorings, and flavorings. In addition, the active compounds may beincorporated into fast dissolved, modified-release or sustained-releasepreparations and formulations, and wherein such sustained-releaseformulations are preferably bi-modal. Preferred tablets contain lactose,cornstarch, magnesium silicate, croscarmellose sodium, povidone,magnesium stearate, or talc in any combination.

Liquid preparations for parenteral administration include sterileaqueous or non-aqueous solutions, suspensions, and emulsions. The liquidcompositions may also include binders, buffers, preservatives, chelatingagents, sweetening, flavoring and coloring agents, and the like.Non-aqueous solvents include alcohols, propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, and organic esters such asethyl oleate. Aqueous carriers include mixtures of alcohols and water,buffered media, and saline. In particular, biocompatible, biodegradablelactide polymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers may be useful excipients tocontrol the release of the active compounds. Intravenous vehicles caninclude fluid and nutrient replenishers, electrolyte replenishers, suchas those based on Ringer's dextrose, and the like. Other potentiallyuseful parenteral delivery systems for these active compounds includeethylene-vinyl acetate copolymer particles, osmotic pumps, implantableinfusion systems, and liposomes.

Alternative modes of administration include formulations for inhalation,which include such means as dry powder, aerosol, or drops. They may beaqueous solutions containing, for example, polyoxyethylene-9-laurylether, glycocholate and deoxycholate, or oily solutions foradministration in the form of nasal drops, or as a gel to be appliedintranasally. Formulations for buccal administration include, forexample, lozenges or pastilles and may also include a flavored base,such as sucrose or acacia, and other excipients such as glycocholate.Formulations suitable for rectal administration are preferably presentedas unit-dose suppositories, with a solid based carrier, and may includea salicylate. Formulations for topical application to the skinpreferably take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Carriers which can be used include petroleumjelly, lanolin, polyethylene glycols, alcohols, or their combinations.Formulations suitable for transdermal administration can be presented asdiscrete patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate  5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced by the same amount ofany of the compounds according to the present invention, in particularby the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 mL.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol andwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol  3 g Lanoline  5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the described inventionmay be varied in many ways by those skilled in the art.

1. A compound of Formula (I):

wherein: G is chosen among N or CR⁷, E is chosen among N or CR⁸,provided that at least one of G or E is N Y is CR⁹, R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸ and R⁹, identical or different, are each independentlyselected in the groups consisted of hydrogen, halogen, —CN,—CF₃—C(═O)R¹⁰, —C(═O)OR¹⁹, —C(═O)NR¹⁰R¹¹, —OR¹⁰, —OC(═O)R¹⁰,—OC(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —NR¹⁰R¹¹,—NR¹⁰C(═O)R¹¹, —NR¹⁰C(═O)OR¹¹, —NR¹⁰S(O)₂R¹¹, an optionally substitutedradical chosen among: —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, or—(C₁-C₆)cyanoalkyl, wherein any two radicals R¹ and R², R³ and R⁴, andR⁵ and R⁶ may be taken together to form an oxo (═O), wherein R¹⁹ andR¹¹, identical or different, are each independently selected fromhydrogen, an optionally substituted radical chosen among: —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₁-C₆)cyanoalkyl, —(C₃-C₇)cycloalkyl or—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, wherein optionally any two radicalsselected from R¹, R², R³, R⁴, R⁵, R⁶, R⁹, R¹⁰ and R¹¹ may be takentogether to form an optionally substituted 3 to 10-membered non-aromaticcarbocyclic or heterocyclic ring or a 5 to 10-membered aromaticheterocyclic ring, n is an integer selected from 0 or 1, Ar¹ is anoptionally substituted aryl or heteroaryl, Ar² is an optionallysubstituted aryl or heteroaryl, and the N-oxide forms thereof, thepharmaceutically acceptable salts and solvates thereof, or their opticalisomers, racemates, diastereoisomers, enantiomers or tautomers thereof.2. A compound according to claim 1, wherein: Ar¹ represents an aryl orheteroaryl chosen among:

wherein m is the number of substituents A on the cycle and is an integerequal to 0, 1, 2, 3, 4 or 5, and/or Ar² represents an aryl or heteroarylchosen among:

wherein p is the number of substituent B on the cycle and is an integerequal to 0, 1, 2, 3, 4 or 5, wherein A and B, identical or different,are each independently selected from the group consisting of hydrogen,halogen, —CN, —NO₂, —OH, —NH₂, —CF₃, an optionally substituted radicalselected from the group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—(C₃-C₈)cycloalkenyl, —(C₁-C₆)cyanoalkyl, —(C₁-C₆)alkylene-heteroaryl,—(C₁-C₆)alkylene-aryl, —(C₁-C₆)alkylene-heterocycle, aryl, heteroaryl,heterocycle, —OR¹³, —(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,—NR¹³(C₂-C₆)alkylene-OR¹⁴, —(C₂-C₆)alkenylene-OR¹³,—(C₂-C₆)alkynylene-OR¹³, —NR¹³R¹⁴, —(C₁-C₆)alkylene-NR¹³R¹⁴,—O—(C₂-C₆)alkylene-NR¹³R¹⁴, —NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵,—(C₂-C₆)alkenylene-NR¹³R¹⁴, —(C₂-C₆)alkynylene-NR¹³R¹⁴, —SR¹³,—(C₁-C₆)alkylene-SR¹³, —O—(C₂-C₆)alkylene-SR¹³,—NR¹³—(C₂-C₆)alkylene-SR¹⁴, —S(═O)—R¹³, —(C₁-C₆)alkylene-S(═O)—R¹³,—O—(C₁-C₆)alkylene-S(═O)—R¹³, —NR¹³—(C₁-C₆)alkylene-S(═O)—R¹⁴,—S(═O)₂—R¹³, —(C₁-C₆)alkylene-S(═O)₂—R¹³, —O—(C₁-C₆)alkylene-S(═O)₂—R¹³,—NR¹³—(C₁-C₆)alkylene-S(═O)₂—R¹⁴, —S(═O)₂NR¹³R¹⁴,—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴, —O—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴,—NR¹³—(C₁-C₆)alkylene-S(═O)₂NR¹⁴R¹⁵, —NR¹³—S(═O)₂R¹⁴,—(C₁-C₆)alkylene-NR¹³—S(═O)₂R¹⁴, —O—(C₂-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—S(═O)₂R¹⁵, —C(═O)—NR¹³R¹⁴,—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴, —O—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,—NR¹³—(C₁-C₆)alkylene-C(═O)—NR¹⁴R¹⁵, —NR¹³C(═O)—R¹⁴,—(C₁-C₆)alkylene-NR¹³C(═O)—R¹⁴, —O—(C₂-C₆)alkylene-NR¹³C(═O)—R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴C(═O)—R¹⁵, —C(═O)—R¹³,—(C₁-C₆)alkylene-C(═O)—R¹³, —O—(C₁-C₆)alkylene-C(═O)—R¹³,—NR¹³—(C₁-C₆)alkylene-C(═O)—R¹⁴, —C(═O)—OR¹³,—(C₁-C₆)alkylene-C(═O)—OR¹³, —O—(C₁-C₆)alkylene-C(═O)—OR¹³,—NR¹³—(C₁-C₆)alkylene-C(═O)—OR¹⁴, —OC(═O)—R¹³,—(C₁-C₆)alkylene-OC(═O)—R¹³, —O—(C₂-C₆)alkylene-OC(═O)—R¹³,—NR¹³—(C₂-C₆)alkylene-OC(═O)—R¹⁴, —NR′³—C(═O)—NR¹⁴R¹⁵,—(C₁-C₆)alkylene-NR¹³—C(═O)—NR¹⁴R¹⁵,—O—(C₂-C₆)alkylene-NR¹³—C(═O)—NR¹⁴R¹⁵,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—C(═O)—NR¹⁵R¹⁶, —NR¹³—C(═O)—OR¹⁴,—(C₁-C₆)alkylene-NR¹³—C(═O)—OR¹⁴, —O—(C₂-C₆)alkylene-NR¹³—C(═O)—OR¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—C(═O)—OR¹⁵, —O—C(═O)—NR¹³R¹⁴,—(C₁-C₆)alkylene-O—C(═O)—NR¹³R¹⁴, —O—(C₂-C₆)alkylene-O—C(═O)—NR¹³R¹⁴,—NR¹³—(C₂-C₆)alkylene-O—C(═O)—NR¹⁴R¹⁵, —C(═O)—(C₁-C₆)alkylene-NR¹³R¹⁴,—(C₁-C₆)alkylene-C(═O)—(C₁-C₆)alkylene-NR¹³R¹⁴,—C(═O)—(C₁-C₆)alkylene-OR¹³,—(C₁-C₆)alkylene-C(═O)—(C₁-C₆)alkylene-OR¹³, —NR¹³—C(═S)—NR¹⁴R¹⁵,—(C₁-C₆)alkylene-NR¹³—C(═S)—NR¹⁴R¹⁵, —NR¹³—C(═NR¹⁴)—NR¹⁵R¹⁶ or—(C₁-C₆)alkylene-NR¹³—C(═NR¹⁴)—NR¹⁵R¹⁶; wherein R¹³, R¹⁴, R¹⁵ and R¹⁶are each independently selected from hydrogen, an optionally substituted—(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl,aryl, heterocycle, —(C₁-C₆)alkylene-heteroaryl,—(C₁-C₆)alkylene-heterocycle and —(C₁-C₆)alkylene-aryl; whereinoptionally any two radicals selected from R¹³, R¹⁴, R¹⁵ or R¹⁶ may betaken together to form a 3 to 10-membered carbocycle, heterocycle, arylor heteroaryl ring; wherein each ring is optionally further substitutedwith 1 to 5 radicals independently selected from halogen, cyano, nitro,hydroxyl, amino, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;wherein any two radicals A and any two radicals B may be combined withthe intervening atoms to form a 3 to 10-membered carbocycle,heterocycle, aryl or heteroaryl ring; wherein each ring is optionallyfurther substituted with 1 to 5 radicals independently selected fromhalogen, —CN, hydroxyl, amino, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and—N—((C₁-C₆)alkyl)₂.
 3. A compound according to claim 1 or 2, of Formula(II):

wherein Ar¹ represents an aryl or heteroaryl chosen among:

Wherein: m is the number of substituents A on the cycle and is aninteger equal to 0, 1, 2, 3 or 4, A, identical or different, are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —CF₃, —OH, —NH₂, an optionally substituted radical selected fromthe group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-heterocycle,heterocycle, aryl, heteroaryl, —OR¹³, —(C₁-C₆)alkylene-OR¹³,—O—(C₂-C₆)alkylene-OR¹³, —NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴,—(C₁-C₆)alkylene-NR¹³R¹⁴, —O—(C₂-C₆)alkylene-NR¹³R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —SR¹³, —(C₁-C₆)alkylene-SR¹³,—O—(C₂-C₆)alkylene-SR¹³, —NR¹³—(C₂-C₆)alkylene-SR¹⁴, —S(═O)—R¹³,—S(═O)₂—R¹³, —S(═O)₂NR¹³R¹⁴, —(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴,—NR¹³—S(═O)₂R¹⁴, —(C₁-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,—O—(C₂-C₆)alkylene-NR¹³—S(═O)₂R¹⁴, —NR¹³—(C₂-C₆)alkylene-NR¹⁴—S(═O)₂R¹⁵,—C(═O)—NR¹³R¹⁴, —(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,—O—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴, —NR¹³—(C₁-C₆)alkylene-C(═O)—NR¹⁴R¹⁵,—NR¹³C(═O)—R¹⁴, —(C₁-C₆)alkylene-NR¹³C(═O)—R¹⁴,—O—(C₂-C₆)alkylene-NR¹³C(═O)—R¹⁴, —NR¹³—(C₂-C₆)alkylene-NR¹⁴C(═O)—R¹⁵,—C(═O)—R¹³, —C(═O)—OR¹³, —(C₁-C₆)alkylene-C(═O)—OR¹³,—O—(C₁-C₆)alkylene-C(═O)—OR¹³, —NR¹³—(C₁-C₆)alkylene-C(═O)—OR¹⁴,—OC(═O)—R¹³, —(C₁-C₆)alkylene-OC(═O)—R¹³, —O—(C₂-C₆)alkylene-OC(═O)—R¹³,—NR¹³—(C₂-C₆)alkylene-OC(═O)—R¹⁴ or —NR¹³—C(═O)—OR¹⁴; wherein R¹³, R¹⁴and R¹⁵ are each independently selected from hydrogen, an optionallysubstituted —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl, aryl, heterocycle,—(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-heterocycle and—(C₁-C₆)alkylene-aryl; wherein optionally any two radicals selected fromR¹³, R¹⁴ or R¹⁵ on substituent A may be taken together to form a 3 to10-membered carbocycle, heterocycle, aryl or heteroaryl ring; whereineach ring is optionally further substituted with 1 to 5 radicalsindependently selected from halogen, —CN, —NO₂, —OH, —NH₂,—(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂; wherein any tworadicals A may be combined with the intervening atoms to form a 3 to10-membered carbocycle, heterocycle, aryl or heteroaryl ring; whereineach ring is optionally further substituted with 1 to 5 radicalsindependently selected from halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂; and/or Ar² represents an aryl orheteroaryl chosen among:

wherein p is the number of substituent B on the cycle and is an integerequal to 0, 1, 2, 3, 4 or 5, B, identical or different, are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —CF₃, an optionally substituted radical selected from the group of—(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-heterocycle,—(C₁-C₆)alkylene-aryl, heterocycle, —OR¹³, —(C₁-C₆)alkylene-OR¹³,—O—(C₂-C₆)alkylene-OR¹³, —NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴,—(C₁-C₆)alkylene-NR¹³R¹⁴, —O—(C₂-C₆)alkylene-NR¹³R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —SR¹³, —(C₁-C₆)alkylene-SR¹³,—O—(C₂-C₆)alkylene-SR¹³, —NR¹³—(C₂-C₆)alkylene-SR¹⁴, —S(═O)—R¹³,—(C₁-C₆)alkylene-S(═O)—R¹³, —O—(C₁-C₆)alkylene-S(═O)—R¹³,—NR¹³—(C₁-C₆)alkylene-S(═O)—R¹⁴, —S(═O)₂—R¹³,—(C₁-C₆)alkylene-S(═O)₂—R¹³, —O—(C₁-C₆)alkylene-S(═O)₂—R¹³,—NR¹³—(C₁-C₆)alkylene-S(═O)₂—R¹⁴, —S(═O)₂NR¹³R¹⁴,—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴, —O—(C₁-C₆)alkylene-S(═O)₂NR¹³R¹⁴,—NR¹³—(C₁-C₆)alkylene-S(═O)₂NR¹⁴R¹⁵, —NR¹³—S(═O)₂R′⁴,—(C₁-C₆)alkylene-NR¹³—S(═O)₂R¹⁴, —O—(C₂-C₆)alkylene-NR¹³—S(═O)₂R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—S(═O)₂R¹⁵, —C(═O)—NR¹³R¹⁴,—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴, —O—(C₁-C₆)alkylene-C(═O)—NR¹³R¹⁴,—NR¹³—(C₁-C₆)alkylene-C(═O)—NR¹⁴R¹⁵, —NR¹³C(═O)—R¹⁴,—(C₁-C₆)alkylene-NR¹³C(═O)—R¹⁴, —O—(C₂-C₆)alkylene-NR¹³C(═O)—R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴C(═O)—R¹⁵, —C(═O)—R¹³,—(C₁-C₆)alkylene-C(═O)—R¹³, —O—(C₁-C₆)alkylene-C(═O)—R¹³,—NR¹³—(C₁-C₆)alkylene-C(═O)—R¹⁴, —C(═O)—OR¹³,—(C₁-C₆)alkylene-C(═O)—OR¹³, —O—(C₁-C₆)alkylene-C(═O)—OR¹³,—NR¹³—(C₁-C₆)alkylene-C(═O)—OR¹⁴, —OC(═O)—R¹³,—(C₁-C₆)alkylene-OC(═O)—R¹³, —O—(C₂-C₆)alkylene-OC(═O)—R¹³,—NR¹³—(C₂-C₆)alkylene-OC(═O)—R¹⁴, —(C₁-C₆)alkylene-NR¹³—C(═O)—NR¹⁴R¹⁵,—NR¹³—C(═O)—OR¹⁴, —(C₁-C₆)alkylene-NR¹³—C(═O)—OR¹⁴,—O—(C₂-C₆)alkylene-NR¹³—C(═O)—OR¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴—C(═O)—OR¹⁵, —O—C(═O)—NR¹³R¹⁴,—(C₁-C₆)alkylene-O—C(═O)—NR¹³R¹⁴, —O—(C₂-C₆)alkylene-O—C(═O)—NR¹³R¹⁴,—NR¹³—(C₂-C₆)alkylene-O—C(═O)—NR¹⁴R¹⁵, —C(═O)—(C₁-C₆)alkylene-NR¹³R¹⁴,—C(═O)—(C₁-C₆)alkylene-OR¹³; wherein R¹³, R¹⁴ and R¹⁵ are eachindependently selected from hydrogen, an optionally substituted—(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl, —(C₁-C₆)cyanoalkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl,aryl, heterocycle, —(C₁-C₆)alkylene-heteroaryl,—(C₁-C₆)alkylene-heterocycle and —(C₁-C₆)alkylene-aryl; whereinoptionally any two radicals selected from R¹³, R¹⁴ or R¹⁵ on substituentB may be taken together to form a 3 to 10-membered carbocycle,heterocycle, aryl or heteroaryl ring; wherein each ring is optionallyfurther substituted with 1 to 5 radicals independently selected fromhalogen, —CN, —NO₂, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and—N—((C₁-C₆)alkyl)₂; wherein any two radicals B may be combined with theintervening atoms to form a 3 to 10-membered carbocycle, heterocycle,aryl or heteroaryl ring; wherein each ring is optionally furthersubstituted with 1 to 5 radicals independently selected from halogen,—CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂.4. A compound according to any of claims 1 to 3, wherein: A, identicalor different, are each independently selected from the group consistingof hydrogen, halogen, —CN, —CF₃, —OH, an optionally substituted radicalselected from the group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-heterocycle, heterocycle, —OR¹³, —(C₁-C₆)alkylene-OR¹³,—O—(C₂-C₆)alkylene-OR¹³, —NR¹³(C₂-C₆)alkylene-OR¹⁴,—O(C₂-C₆)alkylene-NR¹³R¹⁴, —NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —NR¹³R¹⁴,—(C₁-C₆)alkylene-NR¹³R¹⁴, —NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴, S(═O)₂NR¹³R¹⁴or —NR¹³—S(═O)₂R¹⁴; wherein R¹³ and R¹⁴ are each independently selectedfrom hydrogen, an optionally substituted —(C₁-C₃)alkyl,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heterocycle and—(C₁-C₆)alkylene-heterocycle; wherein optionally radicals R¹³ and R¹⁴ onsubstituent A may be taken together to form a 3 to 6-memberedcarbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring isoptionally further substituted with 1 to 5 radicals independentlyselected from halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyland —N—((C₁-C₆)alkyl)₂; wherein any two radicals A may be combined withthe intervening atoms to form a 3 to 10-membered carbocycle,heterocycle, aryl or heteroaryl ring; wherein each ring is optionallyfurther substituted with 1 to 5 radicals independently selected fromhalogen, —CN, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;and/or B, identical or different, are each independently selected fromthe group consisting of hydrogen, halogen, —CF₃, —CN, an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-aryl, heterocycle,—OR¹³, —(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,—NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴, —SR¹³, —(C₁-C₆)alkylene-SR¹³,—S(═O)—R¹³, —S(═O)₂—R¹³, —NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴, —C(═O)—OR¹³,—OC(═O)—R¹³, —C(═O)—(C₁-C₆)alkylene-OR¹³ or —C(═O)—R¹³; wherein R¹³ andR¹⁴ are each independently selected from hydrogen, an optionallysubstituted —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl, aryl, heterocycle,—(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-heterocycle and—(C₁-C₆)alkylene-aryl; wherein optionally any two radicals selected fromR¹³ and R¹⁴ on substituent B may be taken together to form a 3 to10-membered carbocycle, heterocycle, aryl or heteroaryl ring; whereineach ring is optionally further substituted with 1 to 5 radicalsindependently selected from halogen, CN, —OH, —NH₂, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂; wherein any two radicals B maybe combined with the intervening atoms to form a 3 to 10-memberedcarbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring isoptionally further substituted with 1 to 5 radicals independentlyselected from halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyland —N—((C₁-C₆)alkyl)₂; and/or only of G or E is N.
 5. A compoundaccording to claim 1 or 2, of Formula (III):

Wherein A, identical or different, are each independently selected fromthe group consisting of hydrogen, halogen, —CN, —CF₃, —OH, an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-heterocycle,heterocycle, —OR¹³, —(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,—NR¹³(C₂-C₆)alkylene-OR¹⁴, —O(C₂-C₆)alkylene-NR¹³R¹⁴,—NR¹³—(C₂-C₆)alkylene-NR¹⁴R¹⁵, —NR¹³R¹⁴, —(C₁-C₆)alkylene-NR¹³R¹⁴,—NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴, S(═O)₂NR¹³R¹⁴ or —NR¹³—S(═O)₂R¹⁴;wherein R¹³ and R¹⁴ are each independently selected from hydrogen, anoptionally substituted —(C₁-C₃)alkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heterocycle and—(C₁-C₆)alkylene-heterocycle; wherein optionally radicals R¹³ and R¹⁴ onsubstituent A may be taken together to form a 3 to 6-memberedcarbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring isoptionally further substituted with 1 to 5 radicals independentlyselected from halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyland —N—((C₁-C₆)alkyl)₂; wherein any two radicals A may be combined withthe intervening atoms to form a 3 to 10-membered carbocycle,heterocycle, aryl or heteroaryl ring; wherein each ring is optionallyfurther substituted with 1 to 5 radicals independently selected fromhalogen, —CN, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂;and/or B, identical or different, are each independently selected fromthe group consisting of hydrogen, halogen, —CF₃, —CN, an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-aryl, heterocycle,—OR¹³, —(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³,—NR¹³(C₂-C₆)alkylene-OR¹⁴, —NR¹³R¹⁴, —SR¹³, —(C₁-C₆)alkylene-SR¹³,—S(═O)—R¹³, —S(═O)₂—R¹³, —NR¹³C(═O)—R¹⁴, —C(═O)—NR¹³R¹⁴, —C(═O)—OR¹³,—OC(═O)—R¹³, —C(═O)—(C₁-C₆)alkylene-OR¹³ or —C(═O)—R¹³; wherein R¹³ andR¹⁴ are each independently selected from hydrogen, an optionallysubstituted —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heteroaryl, aryl, heterocycle,—(C₁-C₆)alkylene-heteroaryl, —(C₁-C₆)alkylene-heterocycle and—(C₁-C₆)alkylene-aryl; wherein optionally any two radicals selected fromR¹³ and R¹⁴ on substituent B may be taken together to form a 3 to10-membered carbocycle, heterocycle, aryl or heteroaryl ring; whereineach ring is optionally further substituted with 1 to 5 radicalsindependently selected from halogen, CN, —OH, —NH₂, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂; wherein any two radicals B maybe combined with the intervening atoms to form a 3 to 10-memberedcarbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring isoptionally further substituted with 1 to 5 radicals independentlyselected from halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyland —N—((C₁-C₆)alkyl)₂; and/or only of G or E is N.
 6. A compoundaccording to any of claims 2 to 5, wherein: A, identical or different,are each independently selected from the group consisting of hydrogen,halogen, —CN, —CF₃, —OH, an optionally substituted radical selected fromthe group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-heterocycle,heterocycle, —O—(C₁-C₆)alkyl, 0-(C₁-C₃)alkyl-(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-OR¹³, —O—(C₂-C₆)alkylene-OR¹³, —NR¹³R¹⁴,—(C₁-C₆)alkylene-NR¹³R¹⁴ or —NR¹³C(═O)—R¹⁴; R¹³ and R¹⁴ are eachindependently selected from hydrogen, an optionally substituted—(C₁-C₃)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl;optionally radicals R¹³ and R¹⁴ on substituent A may be taken togetherto form a 3 to 6-membered carbocycle or heterocycle, wherein each ringis optionally further substituted with 1 to 5 radicals independentlyselected from halogen, —CN, —OH, —NH₂, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyland —N—((C₁-C₆)alkyl)₂; and any two radicals A may be combined with theintervening atoms to form a 3 to 10-membered carbocycle, heterocycle,aryl or heteroaryl ring; wherein each ring is optionally furthersubstituted with 1 to 5 radicals independently selected from halogen,—CN, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂.
 7. Acompound according to any of claims 2 to 6, wherein: B, identical ordifferent, are each independently selected from the group consisting ofhydrogen, halogen, —CF₃, an optionally substituted radical selected fromthe group of —(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, heterocycle, —O—(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl, —O—(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylene-OR¹³, —O—(C₁-C₆)alkylene-aryl,—O—(C₂-C₆)alkylene-O—(C₁-C₆)alkyl, —NR¹³R¹⁴ or —C(═O)—R¹³; R¹³ and R¹⁴are each independently selected from hydrogen, an optionally substituted—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl;optionally radicals R¹³ and R¹⁴ on substituent B may be taken togetherto form a 3 to 6-membered carbocycle, heterocycle, aryl or heteroarylring; wherein each ring is optionally further substituted with 1 to 5radicals independently selected from halogen, —CN, —OH, —NH₂,—(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and —N—((C₁-C₆)alkyl)₂; any two radicalsB may be combined with the intervening atoms to form a 3 to 10-memberedcarbocycle, heterocycle, aryl or heteroaryl ring; wherein each ring isoptionally further substituted with 1 to 5 radicals independentlyselected from halogen, —CN, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl and—N—((C₁-C₆)alkyl)₂.
 8. A compound according to any of claims 1 to 7,wherein: Ar¹ represents an aryl or heteroaryl chosen among:


9. A compound according to any of claims 1 to 8, wherein: Ar² representsan aryl or heteroaryl chosen among:


10. A compound according to any of claims 1 to 9, wherein: R¹, R², R³,R⁴, R⁵ and R⁶ identical or different, are each independently selectedfrom groups consisted of hydrogen, halogen, —OR¹⁰, —NR¹⁰R¹¹, anoptionally substituted —(C₁-C₃)alkyl, any two radicals R¹ and R², R³ andR⁴, and R⁵ and R⁶ may be taken together to form an oxo, and optionallyany two radicals selected from R¹, R², R³, R⁴, R⁵ and R⁶ may be takentogether to form an optionally substituted 3 to 10-membered non-aromaticcarbocyclic or heterocyclic ring;
 11. A compound according to any ofclaims 1 to 10, wherein: R⁷ and R⁸ are selected from groups consisted ofhydrogen, halogen, —CN, —OR¹⁰, —NR¹⁰R¹¹, —CF₃, an optionally substituted—(C₁-C₃)alkyl, wherein R¹⁰ and R¹¹, identical or different, are eachindependently selected from hydrogen, —(C₁-C₃)alkyl or—(C₃-C₇)cycloalkyl, and optionally the two radicals R¹⁰ and R¹¹ may betaken together to form an optionally substituted 3 to 10-memberednon-aromatic carbocyclic or heterocyclic ring;
 12. A compound accordingto any of claims 1 to 11, wherein: R⁹ is selected from groups consistedof hydrogen, halogen, —CN, —OR¹⁰, —NR¹⁰R¹¹, —CF₃, an optionallysubstituted —(C₁-C₃)alkyl, wherein R¹⁰ and R¹¹, identical or different,are each independently selected from hydrogen or —(C₁-C₃)alkyl, andoptionally the two radicals R¹⁰ and R¹¹ may be taken together to form anoptionally substituted 3 to 10-membered non-aromatic carbocyclic orheterocyclic ring.
 13. A compound according to any of claims 1 to 12,wherein R¹ to R⁶ are hydrogen.
 14. A compound according to any of claims1 to 13, wherein R⁷ and R⁸ are hydrogen.
 15. A compound according to anyof claims 1 to 14, wherein R⁹ is hydrogen.
 16. A compound according toany of claims 1 to 15 selected from the following:6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(4-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(+)-6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,(−)-6-(2,4-Dimethyl-phenyl)-2-pyridin-2-yl-5,6,7,8-tetrahydro-2H-phthalazin-1-one,6-(2,4-dimethylphenyl)-2-(5-chlororopyridin-2-yl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one,2-(4-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(3-chloropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(6-fluoropyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(4-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(3-fluoropyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(6-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(4-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(3-methoxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(3-methylpyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)picolinonitrile,6-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile,2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)isonicotinonitrile,2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)nicotinonitrile,6-(2,4-dimethylphenyl)-2-(5-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(4-hydroxypyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-(methoxymethyl)pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(pyridin-3-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(pyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(pyrimidin-5-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(thiazol-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(thiazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(4-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-hydroxypyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-(hydroxymethyl)pyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-methoxy-2-methylphenyl)-2-(4-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-chloropyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-methoxy-2-methylphenyl)-2-(5-methoxypyrazin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-hydroxypyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-methoxy-2-methylphenyl)-2-(4-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(5-methoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(5-methoxy-2-methylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-chloropyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(pyridin-4-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-chloropyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydro-phthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-methoxypyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(4-methoxy-5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-(morpholinomethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-(dimethylamino)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(5-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(pyridin-2-yl)-6-(o-tolyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-cyclopropylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-(1-hydroxyethyl)phenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-cyclopropoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-methoxy-4-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-methoxy-3-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-methoxy-4-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-methoxy-3-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-chloro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(5-methoxy-2-(trifluoromethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-fluoro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-chloro-5-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-methoxy-5-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-methyl-5-(pyrrolidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(1-methylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-fluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(5-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,5-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,3-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-(methoxymethyl)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(5-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-(cyclopentyloxy)phenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(1,5-dimethyl-1H-indazol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-mesityl-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,6-difluoro-3-methoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(1-cyclopropylindolin-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one6-(2-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-(dimethylamino)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(5-methoxy-2,4-dimethylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(4-chloro-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(4-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-(3-methoxypropoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-ethoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-(cyclopropylmethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-isopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-(2-methoxyethoxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-(benzyloxy)-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-cyclopropylpyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-cyclopropylpyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-cyclopropylpyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-cyclopropylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-methoxy-2-methylphenyl)-2-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-methoxy-2-methylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-morpholinopyridin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(5-morpholinopyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-(azetidin-1-yl)pyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,6-(3-methoxy-2-methylphenyl)-2-(5-(2-methoxyethoxy)pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(2-(5-(2-hydroxyethoxy)-pyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(3-acetyl-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-2,5,6,7-tetrahydro-1H-cyclopenta[d]-pyridazin-1-one,7-(2,4-dimethylphenyl)-3-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one,6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-bromopyrimidin-2-yl)-6-(3-cyclopropoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,N-(2-(6-(3-cyclopropoxy-2-methylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,(−)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(−)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(+)-6-(2-chloro-3-cyclopropoxyphenyl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(+6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(+)-6-(3-cyclopropoxy-2-methylphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(−)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(+)-6-(2-chloro-3-methoxyphenyl)-2-(5-methylpyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(−)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,(+)-N-(2-(6-(2,4-dimethylphenyl)-1-oxo-5,6,7,8-tetrahydrophthalazin-2(1H)-yl)pyrimidin-5-yl)acetamide,(+)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,(−)-6-(1-cyclopropyl-1H-indol-4-yl)-2-(pyrimidin-2-yl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-bromopyrimidin-2-yl)-6-(5-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-bromopyridin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-bromopyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-bromopyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,2-(5-bromopyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one,and2-(5-bromo-4-methoxypyrimidin-2-yl)-6-(2,4-dimethylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one.17. A compound according to any of claims 1 to 16, in the form of aracemic mixture or in the form of one or both of the individual opticalisomers.
 18. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to any of claims 1 to 17 and apharmaceutically acceptable excipient.
 19. A compound according to anyof claims 1 to 17 or a pharmaceutical composition according to claim 18for use as a medicament.
 20. A process for preparing the pharmaceuticalcomposition according to claim 18, characterized in that apharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of a compound according to any ofclaims 1 to
 17. 21. A compound or a composition for its use according toclaim 19 to modulate, preferably to reduce or inhibit or negativelymodulate, the activity of metabotropic glutamate receptors, inparticular mGluR7.
 22. A compound or a composition for its use accordingto any of claims 19 and 21 for the prevention or treatment of disordersassociated with glutamate dysfunction in a mammal, including a human.23. A compound or a composition for its use according to any of claims19, 21 and 22 for the prevention or treatment of anxiety disorders suchas agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsivedisorder (OCD), panic disorder, post-traumatic stress disorder (PTSD),social phobia, other phobias; mood disorders including bipolar disorders(I & II), cyclothymic disorder, depression, dysthymic disorder, majordepressive disorder, substance-induced mood disorder, mood disorder dueto a general medical condition, mania, manic depression, seasonalaffective disorders; muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, migraine;disorders selected from the group consisting of neurodegenrativesdisorders such as mild-cognitive impartment, Alzheimer's disease,Parkinson's disease, multiple sclerosis and amyotrophic lateralsclerosis; disorders selected from the group consisting of psychoticdisorders such as schizophrenia, delusional disorder, schizoaffectivedisorder, schizophreniform disorder, substance-induced psychoticdisorder; personality disorders including obsessive-compulsivepersonality disorder, schizoid, schizotypal disorder, borderlinepersonality disorder, anxious-avoidant personality disorder; childhooddisorders including attention-deficit/hyperactivity disorder, mentalretardation, Down's syndrome, tics disorders, autistic spectrumdisorders (such as Rett syndrome or Fragile X syndrome) and autism; oticdisorders including inner ear diseases, disorders, impairments orconditions, such as sensorineural hearing loss, age-related hearingimpairment (presbycusis), Meniere's disease, sudden hearing loss,noise-induced hearing loss, drug-induced hearing loss, hidden hearingloss, cisplatin-induced hearing loss, aminoglycosides-induced hearingloss, otitis media, ototoxicity, autoimmune inner ear disease, acutetinnitus, chronic tinnitus, central auditory processing disorders andvestibular disorders; disorders of the gastrointestinal tract includingdiarrhoea, constipation, gastro-esophageal reflux disease (GERD), loweresophageal sphincter diseases or disorders, diseases of gastrointestinalmotility, colitis, Crohn's disease or irritable bowel syndrome (IBS);pain disorders including acute pain, chronic pain, severe pain,intractable pain, inflammatory pain, post-operative pain, headache pain,cancer pain, neuropathic pain, post-traumatic pain, and visceral pain;cognitive deficit and mood disorders associated with the aforementioneddisorders; ocular disorders including ocular hypertension, glaucoma,normal tension glaucoma, neurodegenerative disease conditions of theretina and the optic nerve, retinal dystrophies, age-related Maculardegeneration, and conditions of the eye such as conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, inflammationand/or neurodegeneration; disorders resulting from traumatic braininjury, stroke, hemorrhagic stroke, ischemia, spinal cord injury,cerebral hypoxia, cerebral hemorrhage or intracranial hematoma.
 24. Useof a compound according to any of claims 1 to 17 as a radiolabeledtracer for imaging metabotropic glutamate receptors, preferably mGluR7in mammal, including human.
 25. Compounds of formula (IV), (V), (VI),(VII), (VIII) or (IX) as intermediates of compounds of formula (I), (II)and (III), wherein G, E, Ar¹, Ar², R¹, R², R³, R⁴, R⁵, R⁶ and Y are asdefined in anyone of claims 1 to 15.